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Peer-reviewedCC BY-NC-NDAnnals of Neurology

Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System

  • Rama K. Koppisetti1,2
  • Nicolas R. Barthélemy3,2
  • Kanta Horie3,2
  • Cindy V. Ly3
  • Kaleigh F. Roberts4
  • Srinivas Koutarapu4
  • Richard J. Perrin5,3,4,6
  • Erin E. Franklin5,4
  • Chiara Pedicone7,8,9
  • Joshua Orrick7,9
  • Justin Melendez3,2
  • Timothy M. Miller3,6
6 more authors
  • Chihiro Sato3,2
  • Nupur Ghoshal3,1
  • Alison Goate7,10,9
  • Celeste M M. Karch5,1
  • Randall John Bateman3,2
  • Soumya Mukherjee3,2
10 affiliations
  1. 1Department of Psychiatry Washington University School of Medicine St. Louis MO USA
  2. 2The Tracy Family Stable Isotope Labeling Quantitation (SILQ) Center Washington University School of Medicine St. Louis MO USA
  3. 3Department of Neurology Washington University School of Medicine St. Louis MO USA
  4. 4Departments of Pathology and Immunology Washington University School of Medicine St. Louis MO USA
  5. 5Charles F. and Joanne Knight Alzheimer Disease Research Center Washington University School of Medicine St. Louis MO USA
  6. 6Hope Center for Neurological Disorders Washington University St. Louis MO USA
  7. 7Departments of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA
  8. 8Neuroscience sperimentali, IRCCS Azienda Ospedaliera Metropolitana, Policlinico San Martino Genoa Italy
  9. 9Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai New York NY USA
  10. 10Nash Family Department of Neuroscience Icahn School of Medicine at Mount Sinai New York NY USA
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Abstract

OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance. METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment. RESULTS: 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 approximately 1,000-fold higher in the 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 approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology. INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and 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. ANN NEUROL 2026;100:709-736.

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Cite

BibTeXRIS
BibTeX
@article{koppisetti2026distribution,
  title = {{Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System}},
  author = {Rama K. Koppisetti and Nicolas R. Barthélemy and Kanta Horie and Cindy V. Ly and Kaleigh F. Roberts and Srinivas Koutarapu and Richard J. Perrin and Erin E. Franklin and Chiara Pedicone and Joshua Orrick and Justin Melendez and Timothy M. Miller and Chihiro Sato and Nupur Ghoshal and Alison Goate and Celeste M M. Karch and Randall John Bateman and Soumya Mukherjee},
  journal = {Annals of Neurology},
  year = {2026},
  month = jul,
  doi = {10.1002/ana.78300},
  url = {https://doi.org/10.1002/ana.78300},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Distribution of Big Tau Isoforms in the Human Central and Peripheral Nervous System
AU  - Rama K. Koppisetti
AU  - Nicolas R. Barthélemy
AU  - Kanta Horie
AU  - Cindy V. Ly
AU  - Kaleigh F. Roberts
AU  - Srinivas Koutarapu
AU  - Richard J. Perrin
AU  - Erin E. Franklin
AU  - Chiara Pedicone
AU  - Joshua Orrick
AU  - Justin Melendez
AU  - Timothy M. Miller
AU  - Chihiro Sato
AU  - Nupur Ghoshal
AU  - Alison Goate
AU  - Celeste M M. Karch
AU  - Randall John Bateman
AU  - Soumya Mukherjee
PY  - 2026
DA  - 2026/07/19
JO  - Annals of Neurology
DO  - 10.1002/ana.78300
UR  - https://doi.org/10.1002/ana.78300
AB  - OBJECTIVE: Tau is widely studied in neurodegeneration, yet most work has focused on canonical brain tau isoforms. A longer isoform, "big tau," produced by inclusion of exon 4a, is expressed in the peripheral nervous system (PNS) and central nervous system (CNS) regions. We sought to characterize big tau composition, anatomic distribution, and disease relevance. METHODS: Mass spectrometry (MS) was used to sequence big tau and map its distribution across the human nervous system. Postmortem samples included brain tissue from Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and controls; spinal cord and peripheral nerves. Big and canonical ("small") tau isoforms were also quantified in cerebrospinal fluid (CSF) from controls and participants stratified by amyloid status and cognitive impairment. RESULTS: 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 approximately 1,000-fold higher in the 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 approximately 1% in the brain, primarily localized to the cerebellum. In CSF, big tau levels were unchanged by amyloid abnormalities or cognitive impairment, whereas canonical tau increased with AD pathology. INTERPRETATION: Big tau represents a distinct tau population enriched in the PNS and 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. ANN NEUROL 2026;100:709-736.
SN  - 0364-5134
SN  - 1531-8249
ER  -