The Contribution of Hematopoietic Aging to the Development of Alzheimer's Disease
Authors: Sreejit Gopalkrishna , Laborc Claudia , Boutajangout Allal , Wisniewski Thomas , Mar Adam , Park Christopher Y. 
Published: December 2024

Alzheimer's disease (AD) is the most common type of dementia and is associated with numerous risk factors including sex, genetic predispositions, environmental factors and immune dysregulation. Increased systemic inflammation associated with aging has widely been thought to promote AD. However, a recent study has shown that clonal hematopoiesis, which is associated with increased systemic inflammation, is negatively associated with AD. Women have a greater lifetime risk of developing AD compared to men and the recently approved anti-amyloid beta (Aβ) AD treatment, Lecanemab, shows sex-dichotomous effects and does not slow cognitive decline in females with AD. Given the potential role of sex and the aging hematopoietic system in the modulation of AD development, we examined the contribution of hematopoietic stem cell (HSC) ageing to AD in male and female engineered mouse models of AD.

To determine the contribution of HSC age and sex to AD development, we transplanted 500 young or 5,000 old HSCs or 5e6 c-Kit+ bone marrow (BM) cells into the APP/PS1 AD mouse model at 6 months of age (a time point after the initial appearance of disease histopathology, but before measurable functional decline). Donors included wild-type (WT) male and female mice and all the transplants were sex-matched. At 3 months post-transplantation, the reconstituted hematopoietic system of transplanted APP/PS1 mice was evaluated by flow cytometry. 5 months post-transplant, an open field test was used to measure locomotor activity and anxiety-like behavior. The rotarod test was used to assess motor skill learning and coordination, while a grip strength test was used to evaluate paw/limb force. Barnes maze test was conducted to assess deficits in learning and memory.

Mice transplanted with WT HSC showed ~60% peripheral blood (PB) donor chimerism, while those transplanted with c-Kit+ BM cells showed ~97% PB donor chimerism at 9 months of age. Recipients of young and old HSCs showed no difference in T-, B- or myeloid cell blood composition when evaluated by flow cytometry. Open Field test 5 months post-transplant, showed no significant difference in the distance traveled between the two groups. No difference in grip strength was observed in mice transplanted with young versus old HSCs when mice were tested 5 months following transplant, irrespective of sex. In Rotarod tests, female APP/PS1 mice receiving old HSC from WT females showed a non-statistically significant trend towards improved motor learning compared to those that had received young HSCs over the training trials; there were no significant differences in motor learning between APP/PS1 mice transplanted with young versus old c-Kit+ cells. The Barnes Maze test, showed that male APP/PS1 mice transplanted with old HSCs performed better than those transplanted with young HSCs as reflected by the significant reduction in latency and errors in locating the target hole, and increase in the proportion of mice that found the hole. These findings are compatible with improved spatial learning and reduced memory deficits following transplantation with old HSCs. In females, although no difference was observed in female APP/PS1 mice transplanted with old versus young HSCs, both groups showed strikingly good learning and memory performance.

Collectively, our studies reveal potential differences in behavioral/cognitive phenotypes when young and old HSCs are transplanted into APP/PS1 mice. HSCs from old mice induce more significant improvements than young HSCs, particularly in male mice. These results suggest that cell-intrinsic alterations in aging HSCs regulate the progression of AD, and that old HSCs protect APP/PS1 mice from disease progression. Moreover, they suggest that such protective effects may be sex dependent.