Tet2 and Jak2 clonal hematopoiesis do not modify murine tauopathy
Abstract
Background: Clonal hematopoiesis (CH) increases with age and elevates the risk of numerous age-associated diseases. However, the association between CH and neurodegenerative diseases has remained unclear. Objective: We tested the association between the presence of CH and tauopathy in a murine model. Methods: We established novel models of Tet2 loss-of-function and Jak2 gain-of-function (V617F) CH in CD45.1-expressing PS19 tauopathy mice using unconditioned bone marrow (BM) cell transfer, thereby maintaining brain integrity, clonal expansion, and enabling mutant cell tracking. Results: In CD45.1- PS19 mice, Tet2 -/- cells (CD45.2) started at a fraction of <2% and clonally expanded in all BM cavities and the blood over 5 months. Tet2 mutant and WT immune cells, however, displayed equivalently low capacity to infiltrate the brain of PS19 mice even with advanced tau deposition. While Tet2 mutant microglia displayed elevated IL1-β production, they comprised a small fraction (3.49 ± 1.35%) relative to the high frequency of mutant monocytes in the blood (26.36 ± 4.33%) of aged CD45.1- PS19 mice after clonal expansion. Jak2 V617F cells (CD45.2) also expanded clonally in the BM and blood over time and had a modestly increased capacity to infiltrate the brain of aged CD45.1- PS19 mice but their proportion among brain microglia remained low (1.12 ± 0.28%) relative to blood monocytes (28.91 ± 4.66%). Critically, Tet2 or Jak2 CH did not alter tau accumulation in the hippocampus or cortex, nor did they influence brain atrophy. Conclusions: Our findings suggest that CH mutant cells do not influx the murine tauopathy brain in large proportions and that CH does not modify neurodegeneration or tau accumulation in mice.
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- Authors
- Gaebel, L., Gerhardt, T., Khamhoung, A., Huynh, P., Heiser, M., Brisnovali, N. F., Jacob, W., Yates, A. G., Douglas, A., Fidler, T., Goedeke, L., & McAlpine, C. S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of California, San Francisco (US)
- Corresponding author
- McAlpine, Cameron S.
- ORCID
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2026-06-18
- Volume
- 112
- Issue
- 3
- Pages
- 1415-1427
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W7165155184
- Cited by
- 1
- References
- 33
- Citations by year
- 2026: 1
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (25AARG-1378979)
- Cure Alzheimer's Fund
- National Institute on Aging (R01AG082185)
- National Heart, Lung, and Blood Institute (R01HL158534, R01HL178835)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- clonal hematopoiesis, TET2
- MeSH terms
- Clonal Hematopoiesis, Animals, Brain, Disease Models, Animal, DNA-Binding Proteins, Humans, Mice, Transgenic, Proto-Oncogene Proteins, tau Proteins, Leukocyte Common Antigens, Tauopathies, Dioxygenases, Mice, Janus Kinase 2
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