Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy

Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy | bioRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-M677548'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy View ORCID Profile Marie H Sabec , Oliver Adam , View ORCID Profile Michael C Ashby doi: https://doi.org/10.1101/2025.05.02.651902 Marie H Sabec University of Bristol Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Marie H Sabec For correspondence: marie.sabec{at}bristol.ac.uk Oliver Adam University of Bristol Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael C Ashby University of Bristol Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael C Ashby Abstract Info/History Metrics Preview PDF Abstract Neurodegenerative tauopathy is associated with impairments in both active axonal trafficking and presynaptic function. Although deficits in axonal trafficking reduce supply of mitochondria to presynaptic sites, where they provide a local source of energy production and calcium homeostasis, it is unclear if this contributes to progressive synaptic impairment driven by aberrant tau. Our in vivo two-photon imaging of mitochondrial movement and calcium dynamics in neocortical neurons of tauopathy mice revealed a progressive tau-driven decrease in axonal mitochondrial trafficking that correlates with disruption of presynaptic activity. Furthermore, we have shown that tau-driven presynaptic dysfunction can be rescued by pharmacological upregulation of axonal mitochondrial trafficking. Therefore, as well as revealing the disruptive influence of tau-induced mitochondrial trafficking impairments on presynaptic function in early stages of tauopathy, these findings highlight the therapeutic potential of targeting axonal trafficking to confer synaptic resilience to pathology. Competing Interest Statement The authors have declared no competing interest. Footnotes Manuscript revised to reflect additional data analysis and inclusion of a new results figure. Funder Information Declared Medical Research Council, https://ror.org/03x94j517 , MR/W005506/1 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . View the discussion thread. Back to top Previous Next Posted May 19, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy Marie H Sabec , Oliver Adam , Michael C Ashby bioRxiv 2025.05.02.651902; doi: https://doi.org/10.1101/2025.05.02.651902 Share This Article: Copy Citation Tools Pharmacological restoration of deficits in mitochondrial trafficking rescues aberrant axonal activity in tauopathy Marie H Sabec , Oliver Adam , Michael C Ashby bioRxiv 2025.05.02.651902; doi: https://doi.org/10.1101/2025.05.02.651902 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Neuroscience Subject Areas All Articles Animal Behavior and Cognition (7618) Biochemistry (17637) Bioengineering (13864) Bioinformatics (41853) Biophysics (21403) Cancer Biology (18540) Cell Biology (25429) Clinical Trials (138) Developmental Biology (13356) Ecology (19862) Epidemiology (2067) Evolutionary Biology (24287) Genetics (15585) Genomics (22464) Immunology (17701) Microbiology (40300) Molecular Biology (17142) Neuroscience (88440) Paleontology (666) Pathology (2825) Pharmacology and Toxicology (4814) Physiology (7633) Plant Biology (15107) Scientific Communication and Education (2042) Synthetic Biology (4285) Systems Biology (9809) Zoology (2268)