Neuron subtypes have distinct mitochondrial transport in axons and vulnerability to tau in vivo

Neuron subtypes have distinct mitochondrial transport in axons and vulnerability to tau in vivo | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (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],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Neuron subtypes have distinct mitochondrial transport in axons and vulnerability to tau in vivo Theresa Niedermeier, Paul Feyen, Katharina Ochs, Thomas Misgeld, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7628051/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Mitochondria are the primary energy producing organelles in eukaryotic cells. Their location is tied to the cell compartment’s energy requirement. Whether mitochondria are actively transported and retain their motility in neuronal axons of adult animals remains debated. Here we show not only a higher fraction of motile axonal mitochondria than currently described, but also marked differences in transport dynamics across neuronal subtypes. We further show that aggregated tau in the Locus Coeruleus (LC), an early pathological hallmark of Alzheimer’s disease, impairs mitochondrial transport along axons, an effect absent in cortical inhibitory and excitatory neurons. Collectively, we demonstrate the abundant and diverse motility of neuronal mitochondria in vivo , and reveal a correlate of LC vulnerability to tau proteinopathy in neurodegenerative diseases. Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration Biological sciences/Neuroscience/Cellular neuroscience Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases/Alzheimer's disease Health sciences/Diseases/Neurological disorders/Neurodegeneration Full Text Additional Declarations There is NO Competing Interest. Supplementary Files VideoS7Fig.3BviSplitonestationaryintwo.mp4 VideoS7_Fig.3B(vi)Split_one_stationary_in_two niedermeieretalFigureS2.pdf Supplementary Figure 2 VideoS3Fig.S3BiiTwodifferentdynamics.mp4 VideoS3_Fig.S3B(ii)Two_different_dynamics VideoS5Fig.S3BivMitochondrialcrossing.mp4 VideoS5_Fig.S3B(iv)Mitochondrial_crossing niedermeieretalFigureS3.pdf Supplementary Figure 3 VideoS6Fig.3BvStopandGo.mp4 VideoS6_Fig.3B(v)Stop_and_Go VideoS4Fig.S3BiiiMergewithstationary.mp4 VideoS4_Fig.S3B(iii)Merge_with_stationary niedermeieretalFigureS9.pdf Supplementary Figure 9 VideoS2Fig.S3BiSpacedoutunilateralTransport.mp4 VideoS2_Fig.S3B(i)Spaced_out_unilateral_Transport niedermeieretalFigureS4.pdf Supplementary Figure 4 niedermeieretalFigureS6.pdf Supplementary Figure 6 VideoS1ExamplePipelineNewUnder30MB.mp4 VideoS1_ExamplePipeline niedermeieretalFigureS7.pdf Supplementary Figure 7 niedermeieretalFigureS1.pdf Supplementary Figure 1 niedermeieretalFigureS5.pdf Supplementary Figure 5: niedermeieretalFigureS10.pdf Supplementary Figure 10 niedermeieretalFigureS8.pdf Supplementary Figure 8 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7628051","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":527238204,"identity":"7d13bd9b-c686-4c08-a255-de50bfb13c19","order_by":0,"name":"Theresa Niedermeier","email":"","orcid":"https://orcid.org/0009-0009-2257-5394","institution":"German Center for Neurodegenerative Diseases (DZNE), Munich","correspondingAuthor":false,"prefix":"","firstName":"Theresa","middleName":"","lastName":"Niedermeier","suffix":""},{"id":527238205,"identity":"58a2fb43-8d18-4fa7-b407-9b1047f454b6","order_by":1,"name":"Paul 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Their location is tied to the cell compartment’s energy requirement. Whether mitochondria are actively transported and retain their motility in neuronal axons of adult animals remains debated. Here we show not only a higher fraction of motile axonal mitochondria than currently described, but also marked differences in transport dynamics across neuronal subtypes. We further show that aggregated tau in the \u003ci\u003eLocus Coeruleus\u003c/i\u003e (LC), an early pathological hallmark of Alzheimer’s disease, impairs mitochondrial transport along axons, an effect absent in cortical inhibitory and excitatory neurons. Collectively, we demonstrate the abundant and diverse motility of neuronal mitochondria \u003ci\u003ein vivo\u003c/i\u003e, and reveal a correlate of LC vulnerability to tau proteinopathy in neurodegenerative diseases.","manuscriptTitle":"Neuron subtypes have distinct mitochondrial transport in axons and vulnerability to tau in vivo","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 10:43:56","doi":"10.21203/rs.3.rs-7628051/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-neuroscience","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"neuro","sideBox":"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)","snPcode":"","submissionUrl":"","title":"Nature Neuroscience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"df56cb2b-c06d-4c7d-b4df-5426d8f3ad17","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56044623,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration"},{"id":56044624,"name":"Biological sciences/Neuroscience/Cellular neuroscience"},{"id":56044625,"name":"Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases/Alzheimer's disease"},{"id":56044626,"name":"Health sciences/Diseases/Neurological disorders/Neurodegeneration"}],"tags":[],"updatedAt":"2025-12-17T18:05:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-15 10:43:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7628051","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7628051","identity":"rs-7628051","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}