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Bone marrow derived immune cell type- and ApoE-isoform specific effects on tauopathy and neuroinflammation in aged mice

Award Number: R21AG096543
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Bone marrow derived immune cell type- and ApoE-isoform specific effects on tauopathy and neuroinflammation in aged mice - ABSTRACT Although Alzheimer's disease (AD) begins with the accumulation of Abeta, brain atrophy and cognitive decline correlate more closely with accumulation of pathologic tau species. Pathologic changes in Abeta and tau are extensively associated with immune responses, primarily involving microglia, which likely are regulated by a relatively small population of lymphoid cells in brain. Human immune response in brain differs from mice both in having multiple ApoE isoforms and bone marrow (BM)-derived microglia along with yolk sac-derived microglia. We thus hypothesize that BM-derived microglia may critically alter ApoE isoform-specific effects relative to yolk sac-derived microglia. Others have shown in the PS19 mouse model of AD-like pathologic tau, that expression of human APOE epsilon 4 exacerbates neurodegeneration and neuroinflammation, which can be ameliorated by depletion of yolk sac-derived microglia or T cells; however, how this relates to the most common human condition, where microglia may be largely BM-derived, remains unknown. We propose a minimally toxic conditioning protocol for bone BM transplantation (BMT), which is routinely used for immunomodulation in patients with non-neoplastic, chronic diseases. We hypothesize that BM-derived microglia critically may alter ApoE isoform-specific effects relative to yolk sac-derived microglia. Aim 1 will determine whether BM-derived cell ApoE-specific effects are necessary to increase injury or sufficient for protection in aged PS19 mice. In Aim 1 we will determine whether BM-derived cells from APOE4-KI mice promote pathologic changes, and whether BM-derived cells from apoE-/- mice or mice expressing APOE2 knock in (KI) protect from these changes and accompanying behavioral impairment. In Aim 2 we will perform comprehensive transcriptomic analysis to profile the diversity of engrafted cells and compare donor and resident cells at single cell resolution in the context of pathologic tau-mediated neurodegeneration and neuroinflammation. These cell type-specific transcriptomic data will be integrated with immunofluorescent images to visualize structural differences between donor and resident cells, map their number and distribution within brain regions, and quantify changes by proximity to pathologic tau. When successfully completed, our project will provide key mechanistic insights into human vs. mouse immune cell response(s) to pathologic tau, guiding design of future work that maintains focus on human-relevant immune responses in models of AD neurodegeneration. 1


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $428,707 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	1	9/14/2026	NEW	$428,707
														Subtotal = $428,707

Grand Total All Awards = $428,707

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Bone marrow derived immune cell type- and ApoE-isoform specific effects on tauopathy and neuroinflammation in aged mice

Award Number: R21AG096543

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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