{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:10:15Z","timestamp":1792786215062,"version":"4.5.0"},"posted":{"date-parts":[[2025,9,17]]},"group-title":"Neuroscience","reference-count":99,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["P41 GM103422"],"award-info":[{"award-number":["P41 GM103422"]}]},{"name":"National Institute of Health","award":["P01 AG03991"],"award-info":[{"award-number":["P01 AG03991"]}]},{"name":"National Institute of Health","award":["NS110890"],"award-info":[{"award-number":["NS110890"]}]},{"name":"National Institute of Health","award":["NS123985"],"award-info":[{"award-number":["NS123985"]}]},{"name":"National Institute of Health","award":["P30 AG066444"],"award-info":[{"award-number":["P30 AG066444"]}]},{"name":"National Institute of Health","award":["P01 AG026276"],"award-info":[{"award-number":["P01 AG026276"]}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS095773"],"award-info":[{"award-number":["R01NS095773"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["1U54NS123746-01"],"award-info":[{"award-number":["1U54NS123746-01"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Clinical and Translational Science Awards","award":["UL1TR004419"],"award-info":[{"award-number":["UL1TR004419"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Tau is widely studied in the field of neurodegenerative disease research, yet most work has focused on canonical brain tau isoforms. A longer isoform, \u201cbig tau,\u201d produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and select central nervous system (CNS) regions. We sought to characterize big tau molecular composition, anatomical distribution, and relevance to neurodegenerative disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Mass spectrometry was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer\u2019s disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord from ALS and controls; and peripheral nerves. Big and canonical (\u201csmall\u201d) tau isoforms were also quantified in cerebrospinal fluid (CSF) from young controls and participants stratified by amyloid status and cognitive impairment.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Human big tau results from insertion of either 355 or 251 amino acids encoded by exon 4a-long and exon 4a-short, respectively. Alternative splicing of exons 2, 3, and 10 generates multiple big tau isoforms. Total tau levels were \u223c1000-fold higher in brain than in the PNS; however, the relative abundance of big tau increased from the CNS to the PNS, comprising 50 % of the total tau in the periphery and exhibiting considerable regional heterogeneity in the brain (\u223c 1 % of total tau). In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD-related pathology.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>Big tau represents a distinct tau population enriched in the PNS and largely uncoupled from disease-associated changes in brain-derived tau, suggesting that distinguishing big tau from canonical tau may improve interpretation of tau biomarkers and help differentiate CNS neurodegeneration from peripheral nerve pathology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.15.676127","type":"posted-content","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T22:35:12Z","timestamp":1758148512000},"source":"Crossref","is-referenced-by-count":3,"title":["Distribution of big tau isoforms in the human central and peripheral nervous system"],"prefix":"10.64898","author":[{"given":"Rama Krishna","family":"Koppisetti","sequence":"first","affiliation":[{"name":"The Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center, Washington University School of Medicine, Saint. 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