Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy
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Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.
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Blockade of low-affinity FcγII/III receptors largely prevents antibody uptake.
“Fc receptors are expressed on neurons231,232 and seem to be the main route of entry for anti-tau antibodies: blockade of low-affinity FcγII/III receptors largely prevents antibody uptake202,219.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [219]
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Xu, Z., Shalin, K., Do, V., Yan, A., & Gao, J. (2026) · doi:10.64898/2026.05.29.728695
- Authors
- Kondo, A., Shahpasand, K., Mannix, R., Qiu, J., Moncaster, J., Chen, C.-H., Yao, Y., Lin, Y.-M., Driver, J. A., Sun, Y., Wei, S., Luo, M.-L., Albayram, O., Huang, P., Rotenberg, A., Ryo, A., Goldstein, L. E., Pascual-Leone, A., McKee, A. C., Meehan, W., Zhou, X. Z., & Lu, K. P.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Boston University (US)
- Yokohama City University (JP)
- Corresponding author
- Zhou, Xiao Zhen
- Lu, Kun Ping
- ORCID
- Venue
- Nature
- Published
- 2015-07
- Volume
- 523
- Issue
- 7561
- Pages
- 431-436
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4718588
- OpenAlex
- W1590917599
- Cited by
- 445
- References
- 62
- Citations by year
- 2026: 11 · 2025: 24 · 2024: 40 · 2023: 42 · 2022: 38 · 2021: 35 · 2020: 54 · 2019: 44 · 2018: 52 · 2017: 47 · 2016: 48 · 2015: 10
- FWCI
- 38.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG029385, R01AG046319, P30AG013846, P30-AG13846))
- National Heart, Lung, and Blood Institute (R01HL111430)
- National Cancer Institute (R01CA167677)
- National Institute of Neurological Disorders and Stroke (U01NS086659)
- National Center for Research Resources (S10RR017927)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD040128)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, tauopathy, phosphorylated tau, chronic traumatic encephalopathy, Alzheimer's disease, neurodegeneration, mitochondrial transport, neuronal apoptosis, antibody therapy, tau spread
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Monoclonal, Antibody Affinity, Epitopes, Axons, Brain, Brain Injuries, Disease Models, Animal, Female, Humans, Male, Phosphoproteins, Stress, Physiological, tau Proteins, Tauopathies, Mice
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