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Impact of the gut microbiome on B cell-mediated neuroinflammation in cerebral amyloid angiopathy

Award Number: R01AG085585
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Impact of the gut microbiome on B cell-mediated neuroinflammation in cerebral amyloid angiopathy - PROJECT SUMMARY Recent studies exploring the mechanisms that facilitate the crosstalk between the brain and the gut microbiota have demonstrated the importance of the “microbiota-gut-brain axis” (MGBA) in aging and age-related neurodegenerative disorders. The MGBA plays key regulatory roles in aging and in the development and progression of neurological diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). CAA is an age-related small vessel disease characterized by amyloid-beta (Aβ) accumulation in the basement membrane of the brain vasculature. CAA is a primary contributor to the pathophysiology of recurrent intracerebral hemorrhages, stroke, and progressive cognitive decline in the elderly. Several recent studies have highlighted the detrimental role of lymphocytes in the context of AD and related dementias. Regarding the specific role of B cells, prior studies have shown that depletion of B cells reduced Aβ plaque burden, disease-associated microglia, and reversed cognitive and memory impairment in murine models. B cells are multifunctional cells that are integral to host adaptive and humoral immunity. They mount antigen- specific responses to clear pathogens via phagocytosis and antibody dependent cellular cytotoxicity. Our preliminary studies revealed that symptomatic Tg-SwDI mice (CAA mice; 10-13 months) have 1) increased CD19+ cells (B cells) in immune compartments of the central nervous system including the brain and skull and 2) dysbiotic bacterial compositions in the gut, compared with pre-symptomatic CAA mice (2 months) and age- matched wild-type (WT) mice (10-13 months). Surprisingly, fecal microbiota transplantation (FMT) from symptomatic CAA mice increased the presence of brain B cells in recipient young naïve WT mice. These mice developed significant cognitive deficits when compared to young WT mice that received FMT from pre- symptomatic CAA mice. Based on our findings, we propose to test the following hypotheses using a mouse model of CAA: (1) CAA induces B cell-driven inflammation in the brain; (2) CAA-induced gut dysbiosis can promote B cell-mediated neuroinflammation which contributes to the pathogenesis and progression of CAA; and (3) targeting B cells can limit CAA pathophysiology. Successful completion of our study will discover new mechanisms that may allow us to target brain B cells to improve outcome in CAA. These studies will also serve as an important initial step in understanding the bidirectional role of brain-gut axis in the development of age-related chronic neuroinflammatory conditions such as CAA and AD.


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 = $696,896 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	2	2/26/2026	NON-COMPETING CONTINUATION	$69,689
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	2	1/14/2026	NON-COMPETING CONTINUATION	$627,207
														Subtotal = $696,896

Issue Date FY: 2025 ( Subtotal = $696,896 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	12/31/2024	NEW	$696,896
														Subtotal = $696,896

Grand Total All Awards = $1,393,792

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Impact of the gut microbiome on B cell-mediated neuroinflammation in cerebral amyloid angiopathy

Award Number: R01AG085585

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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