DOI: 10.1177/13872877261458734 ISSN: 1387-2877
Tet2
and
Jak2
clonal hematopoiesis do not modify murine tauopathy
Lena Gaebel, Teresa Gerhardt, Annie Khamhoung, Pacific Huynh, Merlin Heiser, Niki F. Brisnovali, Walter Jacob, Abi G. Yates, Aaron Douglas, Trevor Fidler, Leigh Goedeke, Cameron S. McAlpine
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.