Seizures are a druggable mechanistic link between TBI and subsequent tauopathy

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The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we tes …"><meta name="keywords" content="pmid:33527898, PMC7853719, doi:10.7554/eLife.58744, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Hadeel Alyenbaawi, Richard Kanyo, W Ted Allison, Animals, Animals, Genetically Modified, Anticonvulsants / pharmacology, Brain Injuries, Traumatic / complications*, Cell Death / drug effects, Dynamins / antagonists & inhibitors, Green Fluorescent Proteins / genetics, Larva, Mice, Seizures / complications*, Seizures / drug therapy, Tauopathies / drug therapy*, Tauopathies / etiology, Zebrafish, tau Proteins / metabolism, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Seizures are a druggable mechanistic link between TBI and subsequent tauopathy - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/33527898/"><meta property="og:description" content="Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we tes …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Seizures are a druggable mechanistic link between TBI and subsequent tauopathy - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/33527898/"><meta name="twitter:description" content="Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we tes …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">  <link rel="search" type="application/opensearchdescription+xml" href="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/opensearch.xml" title="PubMed search">  <noscript> <link rel="stylesheet" type="text/css" href="https://cdn.ncbi.nlm.nih.gov/pubmed/ed1a5a1f-b279-475e-88e3-75f261729818/core/no-script.css"> </noscript> <meta name="citation_title" content="Seizures are a druggable mechanistic link between TBI and subsequent tauopathy"> <meta name="citation_authors" content="Alyenbaawi H;Kanyo R;Locskai LF;Kamali-Jamil R;DuVal MG;Bai Q;Wille H;Burton EA;Allison WT;"> <meta name="citation_date" content="02/02/2021"> <meta name="citation_publisher" content="Elife"> <meta name="citation_journal_title" content="eLife"> <meta name="citation_pmid" content="33527898"> <meta name="citation_abstract_html_url" content="https://pubmed.ncbi.nlm.nih.gov/33527898/"> <meta name="citation_volume" content="10"> <meta name="citation_doi" content="10.7554/eLife.58744"> <meta name="citation_issn" content="2050-084X"> <link rel="canonical" href="https://pubmed.ncbi.nlm.nih.gov/33527898/" /> </head> <body > <noscript> <div class="no-script-banner" id="no-script-banner"> <div class="warning-message"> <div class="warning-message-text"> This site needs JavaScript to work properly. 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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="GL1IsXoWyA5oGJkZKUMml3JNkBiPpp54fRU6Dw1gijLNp5JLj02GQl2wdiuhh2bF"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="GL1IsXoWyA5oGJkZKUMml3JNkBiPpp54fRU6Dw1gijLNp5JLj02GQl2wdiuhh2bF"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="GL1IsXoWyA5oGJkZKUMml3JNkBiPpp54fRU6Dw1gijLNp5JLj02GQl2wdiuhh2bF"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="GL1IsXoWyA5oGJkZKUMml3JNkBiPpp54fRU6Dw1gijLNp5JLj02GQl2wdiuhh2bF"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="33527898"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Elife%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22Elife%22%5Bjour%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_journal_name_link&journal_abbrev=Elife" data-ga-category="search" data-ga-action="journal_link" data-ga-label="Elife"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Elife%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Elife"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Elife"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Elife"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2021 Feb 2:10:e58744.</span> </div> <span class="citation-doi"> doi: 10.7554/eLife.58744. </span> </div> <h1 class="heading-title"> Seizures are a druggable mechanistic link between TBI and subsequent tauopathy </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Alyenbaawi+H&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hadeel Alyenbaawi">Hadeel Alyenbaawi</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medical Genetics, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Majmaah University, Majmaah, Saudi Arabia." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kanyo+R&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Richard Kanyo">Richard Kanyo</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Locskai+LF&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Laszlo F Locskai">Laszlo F Locskai</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kamali-Jamil+R&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Razieh Kamali-Jamil">Razieh Kamali-Jamil</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=DuVal+MG&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michèle G DuVal">Michèle G DuVal</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Bai+Q&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Qing Bai">Qing Bai</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neurology, University of Pittsburgh, Pittsburgh, United States." href="#full-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Wille+H&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Holger Wille">Holger Wille</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Burton+EA&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Edward A Burton">Edward A Burton</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neurology, University of Pittsburgh, Pittsburgh, United States." href="#full-view-affiliation-6" ref="linksrc=author_aff"> 6 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Geriatric Research, Education and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, United States." href="#full-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Allison+WT&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="W Ted Allison">W Ted Allison</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medical Genetics, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup></span> </div> </div> </div> <div class="short-article-details"> Affiliations <button class="more-details" id="toggle-authors" data-alt-text="Collapse" aria-controls="expanded-authors" aria-expanded="false" data-pinger-ignore data-fetch-url="/33527898/long-authors/" data-id-prefix=""> <span class="title"> Expand </span> </button> </div> <div class="extended-article-details" id="expanded-authors" aria-hidden="true"> <div class="expanded-authors" id="full-view-expanded-authors"> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="full-view-affiliation-1" id="full-view-affiliation-1" ><sup class="key">1</sup> Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="full-view-affiliation-2" id="full-view-affiliation-2" ><sup class="key">2</sup> Department of Medical Genetics, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="full-view-affiliation-3" id="full-view-affiliation-3" ><sup class="key">3</sup> Majmaah University, Majmaah, Saudi Arabia.</li> <li data-affiliation-id="full-view-affiliation-4" id="full-view-affiliation-4" ><sup class="key">4</sup> Department of Biological Sciences, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="full-view-affiliation-5" id="full-view-affiliation-5" ><sup class="key">5</sup> Department of Biochemistry, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="full-view-affiliation-6" id="full-view-affiliation-6" ><sup class="key">6</sup> Department of Neurology, University of Pittsburgh, Pittsburgh, United States.</li> <li data-affiliation-id="full-view-affiliation-7" id="full-view-affiliation-7" ><sup class="key">7</sup> Geriatric Research, Education and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, United States.</li> </ul> </div> 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id="short-view-heading"> <h1 class="heading-title"> Seizures are a druggable mechanistic link between TBI and subsequent tauopathy </h1> <div class="short-citation"> <span class="authors-list"> <span class="authors-list-item "><span class="full-name">Hadeel Alyenbaawi</span><span class="citation-separator"> et al.</span></span> </span> <span class="citation-journal"> Elife<span class="citation-separator">.</span> </span> <span class="date"> <time class="citation-year" datetime="2021">2021</time><span class="citation-separator">.</span> </span> </div> <div class="more-article-details-section with-display-settings"> <button class="more-article-details" id="toggle-article-details" data-alt-text="Hide details" ref="linksrc=toggle_article_details" aria-controls="full-article-details" aria-expanded="false" data-fetch-url="/33527898/long-authors/" data-id-prefix=""> <span class="title">Show details</span> </button> <div class="display-options" data-format-key="format" 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class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medical Genetics, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Majmaah University, Majmaah, Saudi Arabia." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kanyo+R&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Richard Kanyo">Richard Kanyo</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Locskai+LF&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Laszlo F Locskai">Laszlo F Locskai</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kamali-Jamil+R&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Razieh Kamali-Jamil">Razieh Kamali-Jamil</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=DuVal+MG&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Michèle G DuVal">Michèle G DuVal</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Bai+Q&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Qing Bai">Qing Bai</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neurology, University of Pittsburgh, Pittsburgh, United States." href="#short-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Wille+H&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Holger Wille">Holger Wille</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biochemistry, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Burton+EA&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Edward A Burton">Edward A Burton</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Neurology, University of Pittsburgh, Pittsburgh, United States." href="#short-view-affiliation-6" ref="linksrc=author_aff"> 6 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Geriatric Research, Education and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, United States." href="#short-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Allison+WT&cauthor_id=33527898" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="W Ted Allison">W Ted Allison</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Medical Genetics, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, University of Alberta, Edmonton, Canada." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Centre for Prions & Protein Folding Disease, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="short-view-affiliation-2" id="short-view-affiliation-2" ><sup class="key">2</sup> Department of Medical Genetics, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="short-view-affiliation-3" id="short-view-affiliation-3" ><sup class="key">3</sup> Majmaah University, Majmaah, Saudi Arabia.</li> <li data-affiliation-id="short-view-affiliation-4" id="short-view-affiliation-4" ><sup class="key">4</sup> Department of Biological Sciences, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="short-view-affiliation-5" id="short-view-affiliation-5" ><sup class="key">5</sup> Department of Biochemistry, University of Alberta, Edmonton, Canada.</li> <li data-affiliation-id="short-view-affiliation-6" id="short-view-affiliation-6" ><sup class="key">6</sup> Department of Neurology, University of Pittsburgh, Pittsburgh, United States.</li> <li data-affiliation-id="short-view-affiliation-7" id="short-view-affiliation-7" ><sup class="key">7</sup> Geriatric Research, Education and Clinical Center, Pittsburgh VA Healthcare System, Pittsburgh, United States.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">33527898</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC7853719&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7853719/" data-ga-category="full_text" data-ga-action="PMCID" > PMC7853719 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.7554/eLife.58744&id_type=DOI" href="https://doi.org/10.7554/elife.58744" data-ga-category="full_text" data-ga-action="DOI" > 10.7554/eLife.58744 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with full text links" ref="linksrc=full_text_links"> Full text links </button><button class="citation-button citation-dialog-trigger" aria-label="Open dialog with citation text in different styles" data-ga-category="save_share" data-ga-action="cite" data-ga-label="open" data-all-citations-url="/33527898/citations/" data-citation-style="nlm" data-pubmed-format-link="/33527898/export/"><span class="button-label">Cite</span></button><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format" data-default-format-value="abstract" data-current-format-value="abstract" role="region"><button class="trigger usa-button" title="Change format" data-ga-category="display_options" data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title"> Display options </div><div class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Traumatic brain injury (TBI) is a prominent risk factor for dementias including tauopathies like chronic traumatic encephalopathy (CTE). The mechanisms that promote prion-like spreading of Tau aggregates after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative role of seizures in promoting the spread of tauopathy. We introduce 'tauopathy reporter' zebrafish expressing a genetically encoded fluorescent Tau biosensor that reliably reports accumulation of human Tau species when seeded via intraventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI features including cell death, post-traumatic seizures, and Tau inclusions. Bath application of dynamin inhibitors or anticonvulsant drugs rescued TBI-induced tauopathy and cell death. These data suggest a role for seizure activity in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy. </p> </div> <p> <strong class="sub-title"> Keywords: </strong> anti-epileptics; epilepsy; neuroscience; neurotrauma; post-traumatic seizures; tauopathy; traumatic brain injury; zebrafish. </p> </div> <div class="abstract" id="plain-language-summary"> <h2 class="title"> Plain language summary </h2> <p> Traumatic brain injury can result from direct head concussions, rapid head movements, or a blast wave generated by an explosion. Traumatic brain injury often causes seizures in the short term and is a risk factor for certain dementias, including Alzheimer’s disease and chronic traumatic encephalopathy in the long term. A protein called Tau undergoes a series of chemical changes in these dementias that makes it accumulate, form toxic filaments and kill neurons. The toxic abnormal Tau proteins are initially found only in certain regions of the brain, but they spread as the disease progresses. Previous studies in Alzheimer’s disease and other diseases where Tau proteins are abnormal suggest that Tau can spread between neighboring neurons and this can be promoted by neuron activity. However, scientists do not know whether similar mechanisms are at work following traumatic brain injury. Given that seizures are very common following traumatic brain injury, could they be partly responsible for promoting dementia? To investigate this, researchers need animal models in which they can measure neural activity associated with traumatic brain injury and observe the spread of abnormal Tau proteins. Alyenbaawi et al. engineered zebrafish so that their Tau proteins would be fluorescent, making it possible to track the accumulation of aggregated Tau protein in the brain. Next, they invented a simple way to perform traumatic brain injury on zebrafish larvae by using a syringe to produce a pressure wave. After this procedure, many of the fish exhibited features consistent with progression towards dementia, and seizure-like behaviors. The results showed that post-traumatic seizures are linked to the spread of aggregates of abnormal Tau following traumatic brain injury. Alyenbaawi et al. also found that anticonvulsant drugs can lower the levels of abnormal Tau proteins in neurons, preventing cell death, and could potentially ameliorate dementias associated with traumatic brain injury. These drugs are already being used to prevent post-traumatic epilepsy, but more research is needed to confirm whether they reduce the risk or severity of Tau-related neurodegeneration. </p> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">HA, RK, LL, RK, MD, QB, HW, EB, WA No competing interests declared</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="figure-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/8a358c134436/elife-58744-fig1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="676" data-image-height="1170" data-image-alt="Figure 1." data-pmc-id="PMC7853719" data-figure-id="fig1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/027d7eafb815/elife-58744-fig1.gif" alt="Figure 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="676"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1170"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1.. Validating tauopathy fluorescent biosensor in… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1.. Validating tauopathy fluorescent biosensor in vitro and in zebrafish. </p> </strong> <div class="figure-caption-contents"><p> The biosensor Tau4R-GFP was… </p></div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1.. Validating tauopathy fluorescent biosensor in vitro and in zebrafish. </strong> <div class="figure-caption-contents">The biosensor Tau4R-GFP was validated for its ability to detect tauopathy seeds in vitro and in zebrafish. (<b>A</b>) Schematic of Tau4R-GFP ‘Tau biosensor’ that contains the four binding repeats (4R) region of wild-type human Tau linked to green fluorescent protein (GFP; see also Figure 1—figure supplement 1A). (<b>B</b>) Transgenic zebrafish engineered to express Tau4R-GFP biosensor throughout neurons of the CNS. Wild-type GFP is also abundant in the heart, which serves as a marker of the transgene being present but is otherwise irrelevant to our analyses. Scale bar ≅1 mm. (<b>C</b>) Western blot on zebrafish brain confirmed production of Tau4R-GFP at the expected size, similar to a SOD1-GFP biosensor and coordinately larger than GFP alone. (<b>D</b>) Human Tau fibril precipitated from transgenic (Tg Tau<sup>P301L</sup>) mouse brain homogenates using PTA and assessed by EM. (<b>E</b>) Application of PTA-purified brain homogenate induced the formation of Tau inclusions similar to clarified brain homogenate (scale bar 50 μm; compare to Figure 1—figure supplement 1D), but application of equivalent preparations from non-Tg mice produced no GFP+ inclusions. (<b>F–I</b>) Tau biosensor zebrafish detects disease-associated human Tau fibrils following intraventricular injection of brain homogenate. Crude brain homogenates were microinjected into the hindbrain ventricle of Tau4R-GFP zebrafish larvae at 2 days post-fertilization, and Tau inclusions were analyzed at several time points. (<b>F</b>) Tau biosensor zebrafish larvae developed readily apparent GFP+ inclusions in the brain and spinal cord (Figure 1—figure supplement 2) when injected with brain homogenate burdened with Tau pathology (from Tg mice) but not from healthy brain homogenate (F’, from non-Tg mice). <b>F’</b> inset shows many adjacent cells exhibiting GFP+ Tau aggregates. (<b>G</b>) Tau biosensor zebrafish injected with human Tau fibrils (within Tg mouse brain homogenate) developed significantly more aggregates on the spinal cord compared to uninjected control and other control groups, including compared to wildtype mouse brain homogenate (**p=0.0033 ***p=0.0006, ordinary two-way ANOVA and Tukey’s multiple comparison test). (<b>H</b>) Same data as in G, expressed as the percentage of larval fish showing Tau aggregates in the spinal cord, and (<b>I</b>) those same fish also showed Tau aggregates in the brain, over time. n = number of individual larvae. Images in E and F are 5 days post-application or post-injection, respectively.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="figure-1figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/0bc0944f1053/elife-58744-fig1-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="685" data-image-height="661" data-image-alt="Figure 1—figure supplement 1." data-pmc-id="PMC7853719" data-figure-id="fig1s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/5da907aadc6d/elife-58744-fig1-figsupp1.gif" alt="Figure 1—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="685"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="661"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1—figure supplement 1.. Quantification GFP+ inclusions… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1—figure supplement 1.. Quantification GFP+ inclusions in HEK cells expressing Tau4R-GFP biosensor. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A… </b> </p></div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1—figure supplement 1.. Quantification GFP+ inclusions in HEK cells expressing Tau4R-GFP biosensor. </strong> <div class="figure-caption-contents">(<b>A</b>) Schematic of genetically encoded fluorescent Tau4R-GFP ‘Tau Biosensor’ which was produced by fusing the C-terminal four binding repeats (4R) region of wild-type human Tau (Tau4R) to GFP via a linker. This construct was expressed as a transgene (<b>C</b>) in the zebrafish CNS under the promoter enolase 2, and (<b>B</b>) in human embryonic kidney HEK293T cells for validation. (<b>B’</b>) Immunoblot vs. GFP suggests the fusion protein Tau4R-GFP remains intact as a fusion protein when expressed in HEK cells and is an appropriate size (similar to when expressed in zebrafish CNS, Figure 1C). (<b>D</b>) Tau4R-GFP biosensor cells display GFP+ inclusions only upon transduction of crude brain homogenate burdened with tauopathy (from Tg mice expressing human Tau<sup>P301L</sup>), but not when transduced with brain homogenate from normal mice (non-Tg BH). (<b>E</b>) HEK cells from D had a detection rate of approximately 2–3% of cells having GFP+ puncta, whereas various negative controls (no transfection, transfection with PBS only, or transfection of brain homogenate from non-Tg control mice) consistently showed no puncta. For the quantification, the number of cells with inclusions and the number of total cells from nine field images were counted. Bars represents mean of three independent experiments.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="figure-1figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/2bb1447c7938/elife-58744-fig1-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="733" data-image-height="651" data-image-alt="Figure 1—figure supplement 2." data-pmc-id="PMC7853719" data-figure-id="fig1s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/8ddc5158d210/elife-58744-fig1-figsupp2.gif" alt="Figure 1—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="733"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="651"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1—figure supplement 2.. Quantification GFP+ inclusions… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1—figure supplement 2.. Quantification GFP+ inclusions in CNS of zebrafish expressing Tau4R-GFP biosensor, following… </p> </strong> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1—figure supplement 2.. Quantification GFP+ inclusions in CNS of zebrafish expressing Tau4R-GFP biosensor, following injection of human Tau into the zebrafish hindbrain ventricle. </strong> <div class="figure-caption-contents">(<b>A</b>) Schematic showing the microinjections of mouse brain homogenate into the brain ventricles of zebrafish larvae (age is 2 days post-fertilization). Injected material was brain homogenate from transgenic mice expressing human Tau, that is with Tau pathology (e.g. see pathology characterized in Eskandari-Sedighi et al., 2017, DOI 10.1186/s13024-017-0215-7) or brain homogenate from normal control mice. Red fluorescent dye included in the diluted brain homogenate allowed imaging and selection of properly injected embryos. Right: Successfully injected embryos had the injected brain homogenate localized within the zebrafish brain ventricles, with sharp edges and non-diffuse dye. The area encompassing the injected dye is outlined by white dotted lines. (<b>B</b>) Similar to Tau4R-GFP aggregating in the brain, GFP+ aggregates were also detected in the spinal cord following delivery of human Tau, akin to the brain aggregates in Figure 1F. (<b>C</b>) Quantification of spinal cord aggregates. Same data as Figure 1G re-plotted to show the distribution of larvae displaying various quantities of aggregates in the spinal cord. Color coding of treatments equivalent to Figure 1G. Dotted line is hand drawn to emphasize the distribution of larvae injected with tau-burdened brains, compared to various the controls with peak distributions of GFP+ puncta near to zero.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="figure-1figure-supplement-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/861d2f81970c/elife-58744-fig1-figsupp3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="718" data-image-height="681" data-image-alt="Figure 1—figure supplement 3." data-pmc-id="PMC7853719" data-figure-id="fig1s3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/3f994ce4557f/elife-58744-fig1-figsupp3.gif" alt="Figure 1—figure supplement 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="718"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="681"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 1—figure supplement 3.. Movement of some… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 1—figure supplement 3.. Movement of some Tau puncta over time following injection of zebrafish… </p> </strong> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 1—figure supplement 3.. Movement of some Tau puncta over time following injection of zebrafish larvae with brain homogenate burdened with human tauopathy. </strong> <div class="figure-caption-contents">(<b>A</b>) Images of the zebrafish brain area, after injection with Tg hTau<sup>+/p301L</sup> mouse brain homogenate, for the same zebrafish larvae over 3 consecutive days post-injection (dpi), showing the movement of one puncta over time. (<b>B, B’ and B”</b>) The location of Tau aggregates on the spinal cord of three exemplar individual larvae over multiple days, denote movement of some of these puncta over time. Somite numbers were used as landmarks to report the location along the spinal cord over multiple days - somites are blocks of tissue (e.g. muscle) that are readily visible in the trunk of the larva; larger somite number are more posterior (i.e. more distal to the injected brain region) with the most distal region being ‘unsegmented’.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="figure-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/ffe1f9ce2698/elife-58744-fig2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="730" data-image-height="542" data-image-alt="Figure 2." data-pmc-id="PMC7853719" data-figure-id="fig2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/6d1469c72587/elife-58744-fig2.gif" alt="Figure 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="730"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="542"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 2.. Protein-only induction of Tau puncta… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 2.. Protein-only induction of Tau puncta in vivo detected in biosensor zebrafish. </p> </strong> <div class="figure-caption-contents"><p> Injections of… </p></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 2.. Protein-only induction of Tau puncta in vivo detected in biosensor zebrafish. </strong> <div class="figure-caption-contents">Injections of synthetic Tau fibrils into Tau4R-GFP zebrafish induced GFP+ puncta in brains and spinal cord. (<b>A,B</b>) Inhibiting the proteosome with MG-132 enhanced the percentage of larvae bearing GFP+ inclusions in the brain following injection of tau-laden brain homogenate. (<b>C</b>) Synthetic human Tau proteins were fibrillized as confirmed via EM analysis. Human Tau fibrils were microinjected into the larval hindbrain at 2 days post-fertilization, and Tau inclusions were analyzed at 3 days post injections. (<b>D</b>) Tau aggregates were only observed after injection of Tau fibrils, not monomers (*p=0.0104, Kruskal Wallis test). (<b>E</b>) Tau aggregates (same data as D, presented as distribution of larvae that displayed various amounts of GFP+ puncta) appear only after injection of Tau fibrils, not monomers.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="figure-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/77e3c38d8522/elife-58744-fig3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="678" data-image-height="941" data-image-alt="Figure 3." data-pmc-id="PMC7853719" data-figure-id="fig3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/1f604d83796e/elife-58744-fig3.gif" alt="Figure 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="678"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="941"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3.. Zebrafish larvae subjected to traumatic… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3.. Zebrafish larvae subjected to traumatic brain injury (TBI) exhibited various biomarkers of TBI. </p> </strong> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3.. Zebrafish larvae subjected to traumatic brain injury (TBI) exhibited various biomarkers of TBI. </strong> <div class="figure-caption-contents">(<b>A</b>) A novel TBI model for larval zebrafish: to induce blast injury, zebrafish larvae were loaded into a syringe with a stopper. A defined weight was dropped on the syringe plunger from a defined height, producing a pressure wave through the fish body akin to pressure waves experienced during human blast injury. (<b>B</b>) Dynamics of the pressure increase after dropping weights of varying masses in our TBI model. (<b>C,D</b>) The mean and maximum pressures generated, respectively, by various weights applied in the TBI model. Dots represent individual trials. (<b>E</b>) Hemorrhage after TBI was observed in some of the larvae fish using <i>Tg[gata1a:DsRed]</i> transgenic zebrafish that express DsRed in erythrocytes, as indicated by white arrows. Lateral view of larval heads with anterior at the left. Scale bar ≅250 μm. (<b>F</b>) Increased cell death in the brain of 4 dpf larvae subjected to TBI as indicated by immunostaining of activated Caspase-3 (magenta). Positive and negative controls for immunostaining are in supplement. Nuclei were stained with DAPI in gray for reference. These are dorsal views of larval zebrafish brains with anterior at the left. Scale bar is 100 μm. (<b>G</b>) Seizure-like clonic shaking is observed in a subset of larvae after TBI. Movie frames are displayed from Video 2. These frames (left and right panels) are separated by ~400 ms in time, and are lateral views of the larval zebrafish trunk (akin to red box in G’). Control fish without TBI show little movement except obvious blood flow. Following TBI, larvae show bouts of calm (bottom left) interspersed (~400 ms later) with bouts of intense seizure-like convulsions (Stage III seizures; bottom right). (<b>H</b>) Larvae subjected to TBI also displayed Stage II seizures, that is weaker seizures that manifest as hypermotility and are detected using a previously optimized behavioral tracking software system – seizures are significantly more intense following TBI compared to the control group (***p=0.0013, paired t-test; dots are raw data for each larva, mean is plotted ± SE).</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="6" data-label-slug="figure-3figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/53da518bffac/elife-58744-fig3-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-6" role="button" data-image-width="757" data-image-height="969" data-image-alt="Figure 3—figure supplement 1." data-pmc-id="PMC7853719" data-figure-id="fig3s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-6" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/11384903013f/elife-58744-fig3-figsupp1.gif" alt="Figure 3—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="757"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="969"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 3—figure supplement 1.. Traumatic brain injury… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 3—figure supplement 1.. Traumatic brain injury (TBI)-induced cell death. </p> </strong> <div class="figure-caption-contents"><p> Some data copied from Figure… </p></div> </div> <figcaption id="figure-caption-6" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 3—figure supplement 1.. Traumatic brain injury (TBI)-induced cell death. </strong> <div class="figure-caption-contents">Some data copied from Figure 3F here for ease of reference. Increased cell death in the brain of 4 dpf larvae subjected to TBI as indicated by immunostaining of activated Caspase-3 (magenta). Larvae exposed to topoisomerase inhibitor camptothecin (CPT, 3 μM) which induce apoptosis, serves as a positive control. Nuclei were stained with DAPI in gray for reference these are dorsal views of zebrafish brains with anterior at the left.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="7" data-label-slug="figure-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/6e5a1bbea0b0/elife-58744-fig4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-7" role="button" data-image-width="744" data-image-height="1159" data-image-alt="Figure 4." data-pmc-id="PMC7853719" data-figure-id="fig4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-7" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/d0550e9d638c/elife-58744-fig4.gif" alt="Figure 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="744"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1159"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 4.. Neural activity increases during traumatic… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 4.. Neural activity increases during traumatic brain injury (TBI) as measured in CaMPARI zebrafish… </p> </strong> </div> <figcaption id="figure-caption-7" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 4.. Neural activity increases during traumatic brain injury (TBI) as measured in CaMPARI zebrafish larva. </strong> <div class="figure-caption-contents">(<b>A</b>) Schematic of TBI using CaMPARI (Calcium Modulated Photoactivatable Ratiometric Integrator) to optogenetically quantify neuronal excitability. Three dpf CaMPARI larvae were freely swimming while subjected to TBI, coincident with exposure to 405 nm photoconversion light. CaMPARI fluorescence permanently photoconverts from green to red emission only if the photoconversion light is applied while neurons are active (high intracellular [Ca<sup>2+</sup>]). The ratio of red:green emission is stable such that it is quantifiable via subsequent microscopy. (<b>B</b>) Increased neural activity during TBI is represented by increased red:green emission (red pseudocolored to magenta) in the hindbrain of larvae (<b>B”</b>), compared to larvae not receiving TBI (<b>B’</b>) or fish not exposed to photoconverting light (‘no PC’ in panel B). These representative maximum intensity projection images show dorsal view of zebrafish brain (anterior at top), including merged, or red or green channels alone. (<b>C</b>) Heatmaps encode the CaMPARI signal (higher neural activity = higher red:green = hotter colors), highlighting location of increased neural activity during TBI relative to control larvae not receiving TBI. (<b>D</b>) Quantification of CaMPARI output in the hindbrain area reveals a significant increase in the neuronal excitability during TBI compared to control group not receiving TBI (**p=0.0087, Mann-Whitney test. Each data point is an individual larva). Scale bars = 100 μm.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="8" data-label-slug="figure-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/deb7b98958b2/elife-58744-fig5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-8" role="button" data-image-width="723" data-image-height="1374" data-image-alt="Figure 5." data-pmc-id="PMC7853719" data-figure-id="fig5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-8" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/e0a29a9bbe9b/elife-58744-fig5.gif" alt="Figure 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="723"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1374"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5.. Traumatic brain injury (TBI) induces… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5.. Traumatic brain injury (TBI) induces tauopathy in larval zebrafish. </p> </strong> <div class="figure-caption-contents"><p> ( <b> A </b> ) GFP+… </p></div> </div> <figcaption id="figure-caption-8" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5.. Traumatic brain injury (TBI) induces tauopathy in larval zebrafish. </strong> <div class="figure-caption-contents">(<b>A</b>) GFP+ Tau puncta are detected in the brain of Tau4R-GFP biosensor zebrafish at 5 days post-traumatic brain injury (dpti). A 300 g weight was used to induce TBI throughout this figure. (<b>B</b>) Tau aggregates formed on the spinal cord as a result of the TBI as shown by arrows. (<b>C</b>) Tauopathy significantly increases over time following TBI compared to control group (No TBI) *p=0.0264, **p=0.007, two-way ANOVA with Tukey’s multiple comparison test. (<b>D</b>) The number of Tau aggregates in spinal cord significantly increases over time following TBI compared to control group (*p=0.0224 at 3dpti and *p=0.0312 at 4dpti). Inset: Tau4R-GFP zebrafish larvae subjected to TBI develop more GFP+ puncta compared to the control group by 3dpti (inset plot is similar to Figure 2E). Figure 5—figure supplements 2 and 3 plot this in individual fish. (<b>E–H</b>) Post-traumatic seizures link TBI to tauopathy. (<b>E</b>) Following TBI, larvae displaying post-traumatic seizures developed many more Tau aggregates relative to those not displaying post-traumatic seizures (**p=0.0011, Kruskal-Wallis ANOVA with Dunn’s multiple comparison test). (<b>F</b>) Inhibiting post-traumatic seizures with the anti-convulsant retigabine (RTG, 10 μM) significantly decreased the abundance of GFP+ puncta in the spinal cord (p=0.0107, Mann-Whitney test). (<b>G</b>) Increasing post-traumatic seizure using the convulsant kainate (KA, 100 μM; see dose-response in Figure 5—figure supplement 5) significantly increased the formation of Tau aggregation following TBI; this effect was prevented by co-treatment with anti-convulsant RTG. ****p<0.0001, ordinary one-way ANOVA with Tukey’s multiple comparison test. (<b>H</b>) Blunting post-traumatic seizures with RTG reduced TBI-related cell death. The main impact of RTG was specific to its anticonvulsant modulation of seizures because its effects were reversed by convulsant KA. Color scheme in panel C applies to other panels. n = number of zebrafish larvae. ****p<0.0001, ordinary one-way ANOVA with Tukey’s multiple comparison test. Scale bars = 500 μm.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="9" data-label-slug="figure-5figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/0eac898b3a36/elife-58744-fig5-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-9" role="button" data-image-width="642" data-image-height="1608" data-image-alt="Figure 5—figure supplement 1." data-pmc-id="PMC7853719" data-figure-id="fig5s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-9" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/126c442ec4f8/elife-58744-fig5-figsupp1.gif" alt="Figure 5—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="642"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1608"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 1.. Traumatic brain injury… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 1.. Traumatic brain injury (TBI) did not induce GFP+ puncta in transgenic… </p> </strong> </div> <figcaption id="figure-caption-9" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 1.. Traumatic brain injury (TBI) did not induce GFP+ puncta in transgenic zebrafish larvae expressing SOD1-GFP. </strong> <div class="figure-caption-contents">(<b>A, B</b>) TBI did not induce GFP+ puncta in larvae expressing SOD1-GFP, and appeared similar to control larvae that did not experience TBI. (<b>C</b>) Quantification of GFP+ puncta in the spinal cord of SOD1-GFP showing the majority of samples did not develop aggregates post-TBI.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="10" data-label-slug="figure-5figure-supplement-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/e44a87fcc426/elife-58744-fig5-figsupp2.jpg" itemprop="contentUrl" aria-describedby="figure-caption-10" role="button" data-image-width="760" data-image-height="703" data-image-alt="Figure 5—figure supplement 2." data-pmc-id="PMC7853719" data-figure-id="fig5s2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-10" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/9a3f2f0438f4/elife-58744-fig5-figsupp2.gif" alt="Figure 5—figure supplement 2." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="760"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="703"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 2.. Longitudinal analysis of… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 2.. Longitudinal analysis of individual fish after traumatic brain injury (TBI) shows… </p> </strong> </div> <figcaption id="figure-caption-10" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 2.. Longitudinal analysis of individual fish after traumatic brain injury (TBI) shows various patterns of TAu inclusion formation and clearance in their brains. </strong> <div class="figure-caption-contents">(<b>A</b>) In the control group (no TBI) the majority of Tau4R-GFP biosensor larvae did not develop GFP+ aggregates in the brain, although a few either developed aggregates at later time point (3dpi), or developed aggregates that disappeared at later timepoints. (<b>B</b>) Tau4R-GFP biosensor larvae subjected to TBI developed more GFP+ brain aggregates and at earlier timepoints compared to controls, and the number of aggregates typically (although not always) increased with time. Within panels A and B, the left and right graphs are equivalent and display several larvae each.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="11" data-label-slug="figure-5figure-supplement-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/40d8a3f93fda/elife-58744-fig5-figsupp3.jpg" itemprop="contentUrl" aria-describedby="figure-caption-11" role="button" data-image-width="785" data-image-height="724" data-image-alt="Figure 5—figure supplement 3." data-pmc-id="PMC7853719" data-figure-id="fig5s3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-11" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/dfa7e8a8db2d/elife-58744-fig5-figsupp3.gif" alt="Figure 5—figure supplement 3." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="785"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="724"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 3.. Longitudinal analysis of… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 3.. Longitudinal analysis of individual fish after traumatic brain injury (TBI) shows… </p> </strong> </div> <figcaption id="figure-caption-11" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 3.. Longitudinal analysis of individual fish after traumatic brain injury (TBI) shows various patterns of Tau inclusion formation and clearance in their spinal cords. </strong> <div class="figure-caption-contents">(<b>A</b>) Exemplar data from the control group (no TBI) wherein many of the Tau4R-GFP biosensor larvae did not develop aggregates in the spinal cord, while a few either developed aggregates at later timepoints, or developed aggregates that disappeared later on. (<b>B</b>) Tau4R-GFP biosensor larvae subjected to TBI developed more GFP+ spinal cord aggregates and at earlier timepoints compared to controls, and the number of aggregates typically (although not always) increased with time. Within panels A and B, the left and right graphs are equivalent and display several larvae each.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="12" data-label-slug="figure-5figure-supplement-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/d59f92bd6c90/elife-58744-fig5-figsupp4.jpg" itemprop="contentUrl" aria-describedby="figure-caption-12" role="button" data-image-width="794" data-image-height="967" data-image-alt="Figure 5—figure supplement 4." data-pmc-id="PMC7853719" data-figure-id="fig5s4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-12" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/39b91024645c/elife-58744-fig5-figsupp4.gif" alt="Figure 5—figure supplement 4." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="794"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="967"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 4.. Increasing intensity of… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 4.. Increasing intensity of traumatic brain injury (TBI) significantly increased Tau4R-GFP puncta… </p> </strong> </div> <figcaption id="figure-caption-12" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 4.. Increasing intensity of traumatic brain injury (TBI) significantly increased Tau4R-GFP puncta abundance, but only modest insignificant increases in Tau puncta were observed with an increasing number of successive brain injuries. </strong> <div class="figure-caption-contents">(<b>A</b>) Following TBI of Tau4R-GFP larvae, the GFP+ aggregates in the brain tended to be fused. (<b>B,C</b>) Tau4R-GFP larvae were subjected to TBI via either one single hit or five consecutive hits. The number of GFP+ aggregates in the brain (<b>B</b>) and the spinal cord (<b>C</b>) were quantified at 3 and 4 days post-traumatic brain injury (dpi). The number of aggregates modestly increases with more hits but not consistently (not statistically significant). The symbols for treatment types are equivalent in panels <b>B</b> and <b>C</b>. (<b>D</b>) Performing TBI on Tau4R-GFP larvae on each of 3 consecutive days slightly increased the number of GFP+ Tau puncta in the spinal cord (relative to a single TBI treatment) but the increase was not statistically significant. (<b>E</b>) A nearly linear dose-response of TBI injury intensity varying with the abundance of GFP+ puncta in the spinal cord. TBI intensity was modulated by dropping weights of varying masses in the TBI method. Heavier weights induced more GFP+ puncta (*p<0.01 and **p<0.001). In each panel, raw data is plotted, along with mean ± standard error.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="13" data-label-slug="figure-5figure-supplement-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/4ad66ed34f34/elife-58744-fig5-figsupp5.jpg" itemprop="contentUrl" aria-describedby="figure-caption-13" role="button" data-image-width="797" data-image-height="597" data-image-alt="Figure 5—figure supplement 5." data-pmc-id="PMC7853719" data-figure-id="fig5s5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-13" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/661e9a032825/elife-58744-fig5-figsupp5.gif" alt="Figure 5—figure supplement 5." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="797"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="597"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 5—figure supplement 5.. Intensifying seizures following… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 5—figure supplement 5.. Intensifying seizures following traumatic brain injury (TBI) increased abundance of GFP+… </p> </strong> </div> <figcaption id="figure-caption-13" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 5—figure supplement 5.. Intensifying seizures following traumatic brain injury (TBI) increased abundance of GFP+ Tau puncta in a dose-dependent manner. </strong> <div class="figure-caption-contents">Tau4R-GFP larvae were subjected to TBI and post-traumatic seizures were intensified by addition of the convulsant kainate. Although kainate treatment alone (without TBI) did not appreciably increase GFP+ Tau puncta in the spinal cord (black), kainate significantly increased the abundance of puncta in larvae receiving TBI (*p<0.5, **p<0.01, ****p<0.0001 compared to TBI alone [blue text]; #p<0.01 compared to TBI+5 μM dose). Raw data is plotted for each larva, along with mean ± standard error.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="14" data-label-slug="figure-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/1647b65d392a/elife-58744-fig6.jpg" itemprop="contentUrl" aria-describedby="figure-caption-14" role="button" data-image-width="746" data-image-height="1057" data-image-alt="Figure 6." data-pmc-id="PMC7853719" data-figure-id="fig6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-14" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/dfd7e9acec7d/elife-58744-fig6.gif" alt="Figure 6." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="746"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1057"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6.. Tauopathy induced by traumatic brain… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6.. Tauopathy induced by traumatic brain injury (TBI) was attenuated by 4-aminopyridine (4-AP) via… </p> </strong> </div> <figcaption id="figure-caption-14" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6.. Tauopathy induced by traumatic brain injury (TBI) was attenuated by 4-aminopyridine (4-AP) via mechanisms independent of seizures. </strong> <div class="figure-caption-contents">(<b>A</b>) Tau4R-GFP biosensor zebrafish larvae subjected to TBI and treated with the convulsant 4-AP show no brain puncta. Scale bar = 200 μm. (<b>B</b>) 4-AP significantly reduced (apparently eliminated) the abundance of GFP+ puncta in the brain and spinal cord compared to untreated TBI control. Results from alternative doses and timings of 4-AP are reported in Figure 6—figure supplement 1. The impact of 4-AP on tauopathy appears to be independent of its actions on post-traumatic seizures because reducing the latter with anti-convulsant retigabine (RTG) had no measurable effect. (<b>C-F</b>) Pharmacological inhibition of endocytosis reduced tauopathy following TBI. (<b>C</b>) Blocking endocytosis with Pyrimidyn-7 (P7) treatments significantly inhibited the formation of Tau4R-GFP+ puncta following TBI in zebrafish larvae (***p=0.001). (<b>D</b>) Dyngo 4a treatment significantly reduced Tau aggregates in the spinal cord (**p=0.0025) in a manner similar to P7. (<b>E</b>) 4-AP treatment significantly inhibited the formation of Tau4R-GFP+ puncta in the spinal cord (***p=0.0003) of Tau biosensor line that also express human Tau (0N4R) after traumatic brain injury compared to untreated TBI control group. (<b>F</b>) A notable reduction in Tau aggregates was observed in the same line after treatment with P7 drug. Statistical analysis shows no significance difference (ns, p=0.2223) between groups. n = number of larvae. ****p<0.0001, Kruskal-Wallis ANOVA with Dunn’s multiple comparison test used throughout this Figure.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="15" data-label-slug="figure-6figure-supplement-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/30705675c6bd/elife-58744-fig6-figsupp1.jpg" itemprop="contentUrl" aria-describedby="figure-caption-15" role="button" data-image-width="736" data-image-height="1245" data-image-alt="Figure 6—figure supplement 1." data-pmc-id="PMC7853719" data-figure-id="fig6s1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-15" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/02db7cbdb66c/elife-58744-fig6-figsupp1.gif" alt="Figure 6—figure supplement 1." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="736"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="1245"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 6—figure supplement 1.. 4-Aminopuridine (4-AP) abrogates… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 6—figure supplement 1.. 4-Aminopuridine (4-AP) abrogates TBI-induced Tau aggregates when applied at various doses… </p> </strong> </div> <figcaption id="figure-caption-15" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 6—figure supplement 1.. 4-Aminopuridine (4-AP) abrogates TBI-induced Tau aggregates when applied at various doses or for various times. </strong> <div class="figure-caption-contents">(<b>A</b>) Tau4R-GFP biosensor zebrafish larvae subjected to TBI and treated with the convulsant 4-AP show no brain puncta. 4-AP was added to the TBI larvae 1 day post-traumatic brain injury (dpti) and left for 38 hr as displayed in timeline at top. (<b>A,B</b>) 4-AP significantly reduced (apparently eliminated) the abundance of GFP+ puncta in the brain and spinal cord compared to untreated TBI control (**p<0.009 at 3dpti and ***p<0.0003 at 4dpti) at two different doses. (<b>C</b>) All larvae treated with 4-AP failed to display any GFP+ puncta (# of aggregates is 0), displayed as distribution of larvae binned into the number of GFP+ puncta they exhibited. (<b>D,E</b>) Timing and duration of 4-AP treatments following TBI had no appreciable effect on 4-AP abrogating the TBI-induced Tau aggregates. Symbols and colors for all panels are consistent with the legend at the top right of the Figure.</div> </figcaption> </figure> <figure class="figure-item tail" itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="16" data-label-slug="figure-7"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/6d69fdb0367d/elife-58744-fig7.jpg" itemprop="contentUrl" aria-describedby="figure-caption-16" role="button" data-image-width="744" data-image-height="427" data-image-alt="Figure 7." data-pmc-id="PMC7853719" data-figure-id="fig7"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-16" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0064/7853719/c27bc201edff/elife-58744-fig7.gif" alt="Figure 7." /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="744"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="427"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Figure 7.. Graphical summary: anticonvulsants reverse the… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Figure 7.. Graphical summary: anticonvulsants reverse the tauopathy and cell death exhibited by zebrafish larvae… </p> </strong> </div> <figcaption id="figure-caption-16" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Figure 7.. Graphical summary: anticonvulsants reverse the tauopathy and cell death exhibited by zebrafish larvae following traumatic brain injury (TBI). </strong> <div class="figure-caption-contents">Tauopathy was reported via aggregation of a genetically encoded chimeric protein, Tau4R-GFP, that was expressed throughout the central nervous system. TBI led to seizures, and subsequently to Tau aggregation and cell death (akin to chronic traumatic encephalopathy, CTE). The tauopathy and cell death were ameliorated, producing healthy larvae, by blocking seizures with anti-convulsants; these effects were specific insomuch that they could be reversed by co-application of convulsants.</div> </figcaption> </figure> </div> <div class="see-all actions-bar"> <button class="show-more" aria-controls="slides-container" data-ga-category="figure" data-ga-action="show_all"> All figures (17) </button> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button 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Biological Psychiatry. 2018;83:337–346. doi: 10.1016/j.biopsych.2017.04.003. - <a class="reference-link" href="https://doi.org/10.1016/j.biopsych.2017.04.003" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="10.1016/j.biopsych.2017.04.003" > DOI </a> - <a class="reference-link" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5640465/" ref="linksrc=references_link&ordinalpos=2" data-ga-category="reference" data-ga-action="PMC5640465" > PMC </a> - <a class="reference-link" href="/28506438/" ref="linksrc=references_link&ordinalpos=3" data-ga-category="reference" data-ga-action="28506438" > PubMed </a> </li> </ol> </li> <li> <ol class="references-and-notes-list"> <li class="skip-numbering" value="1"> Bai Q, Garver JA, Hukriede NA, Burton EA. Generation of a transgenic zebrafish model of tauopathy using a novel promoter element derived from the zebrafish eno2 gene. Nucleic Acids Research. 2007;35:6501–6516. doi: 10.1093/nar/gkm608. - <a class="reference-link" href="https://doi.org/10.1093/nar/gkm608" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="10.1093/nar/gkm608" > DOI </a> - <a class="reference-link" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2095798/" ref="linksrc=references_link&ordinalpos=2" data-ga-category="reference" data-ga-action="PMC2095798" > PMC </a> - <a class="reference-link" href="/17897967/" ref="linksrc=references_link&ordinalpos=3" data-ga-category="reference" data-ga-action="17897967" > PubMed </a> </li> </ol> </li> <li> <ol class="references-and-notes-list"> <li class="skip-numbering" value="1"> Balik-Meisner M, Truong L, Scholl EH, Tanguay RL, Reif DM. Population genetic diversity in zebrafish lines. Mammalian Genome. 2018;29:90–100. doi: 10.1007/s00335-018-9735-x. - <a class="reference-link" href="https://doi.org/10.1007/s00335-018-9735-x" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="10.1007/s00335-018-9735-x" > DOI </a> - <a class="reference-link" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC5851690/" ref="linksrc=references_link&ordinalpos=2" data-ga-category="reference" data-ga-action="PMC5851690" > PMC </a> - <a class="reference-link" href="/29368091/" ref="linksrc=references_link&ordinalpos=3" data-ga-category="reference" data-ga-action="29368091" > PubMed </a> </li> </ol> </li> <li> <ol class="references-and-notes-list"> <li class="skip-numbering" value="1"> Bir C, Vandevord P, Shen Y, Raza W, Haacke EM. Effects of variable blast pressures on blood flow and oxygen saturation in rat brain as evidenced using MRI. Magnetic Resonance Imaging. 2012;30:527–534. doi: 10.1016/j.mri.2011.12.003. - <a class="reference-link" href="https://doi.org/10.1016/j.mri.2011.12.003" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="10.1016/j.mri.2011.12.003" > DOI </a> - <a class="reference-link" href="/22285875/" ref="linksrc=references_link&ordinalpos=2" data-ga-category="reference" data-ga-action="22285875" > PubMed </a> </li> </ol> </li> </ol> <div class="actions-bar"> <button class="show-all" ref="linksrc=show_all_references_link" aria-controls="top-references-list-1" data-next-page-url="/33527898/references/" data-ga-category="reference" data-ga-action="show_more" > Show all 99 references </button> </div> </div> </div> </div> <div id="publication-types" class="publication-types keywords-section"> <h2 class="title"> Publication types </h2> <ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger 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dropdown-block"><button class="keyword-actions-trigger trigger keyword-link" aria-label="Toggle dropdown menu for keyword tau Proteins / metabolism" tabindex="0" aria-controls="keyword-actions-mesh-terms-14" aria-expanded="false" data-pinger-ignore> tau Proteins / metabolism </button><div id="keyword-actions-mesh-terms-14" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword tau Proteins / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22tau+Proteins%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" data-href="/?term=%22tau+Proteins%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&mesh="tau Proteins/metabolism"[MeSH]" data-ga-category="search" data-ga-action="mesh_term" data-ga-label="tau Proteins / metabolism"> Search in PubMed </a></li><li><a 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