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Endothelial Enhancer of Zeste Homolog 2 in Cerebral Amyloid Angiopathy and Alzheimer's disease

Award Number: R01AG094006
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2030

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Endothelial Enhancer of Zeste Homolog 2 in Cerebral Amyloid Angiopathy and Alzheimer's disease - ABSTRACT Vascular dysfunction is central to the pathology of Cerebral Amyloid Angiopathy (CAA) and Alzheimer’s Disease (AD). Nitric oxide (NO) (produced via nitric oxide synthase), is a vasodilator and signaling molecule essential for the regulation of cerebral blood flow (CBF). Low expression/activity of endothelial NOS (eNOS) contributes to reduced cerebrovascular reactivity, impaired clearance of β-amyloid along the intramural periarterial drainage pathways, and contributes blood-brain barrier (BBB) impairment. Interestingly, cerebral vessels of AD patients have reduced eNOS expression, also known to be controlled by a master epigenetic modifier, enhancer of zeste homolog 2 (EZH2). EHZ2 is a key component of the polycomb repressive complex 2 (PRC2), which catalyzes the trimethylation of lysine 27 in histone 3 (H3K27me3). EZH2 causes transcriptional repression of eNOS and claudin-5, the most enriched tight-junction protein in blood-brain barrier. Our studies revealed significant increase in EZH2 levels and H3K27 trimethylation, its direct target, in the vasculature of Tg-SWDI (CAA model) mice. Importantly, pharmacological inhibition of EZH2 in aged models of CAA and AD (Tg-2576 mice) not only enhances eNOS, but also improves claudin-5, (tight-junction protein). EZH2's role in autoregulation of CBF, BBB integrity and cognition is unknown. The proposal will also reveal new insights into how epigenetic modifications by EZH2 contribute to the sex differences in dementia. We hypothesized that EZH2 is enhanced in models of dementia (CAA model and AD model), leading to decreased eNOS, and reductions in important BBB tight junction proteins(Claudin 5). Enhanced EZH2 contributes to CBF dysregulation, neuroinflammation, and BBB impairment in our established CAA and AD models. Given the increasing incidence of dementia with age, our study will also employ aged transgenic mice of BOTH sexes. Our Specific Aim 1 will determine the role of EZH2 in blood flow autoregulation and its interaction with eNOS in Tg-SwDI and Tg-2576 mice in both sexes. We will test the effect of endothelial EZH2 knockdown (AAV) and pharmacological inhibition in CBF autoregulation in both models. We also hypothesize that EZH2 produces CBF dysregulation by increasing trimethylation at eNOS gene promoter. Our Specific Aim 2 will determine the role of EZH2 in Aβ pathology and BBB integrity in Tg- SwDI and Tg-2576 mice in both sexes. Our Specific Aim 3 will determine if pharmacological EZH2 inhibition and EZH2 KD improve behavioral function in Tg-SwDI and Tg-2576 mice in both sexes. Given EZH2's contribution in key pathological aspects in AD and CAA, we will conduct a series of longitudinal cognitive function tests on aged mice treated with EZH2 inhibitor or endothelial EZH2 KD AAV across both dementia models.


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 = $654,110 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	001	1	1/31/2026	NEW	$0
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Aging Research	000	1	1/23/2026	NEW	$654,110
														Subtotal = $654,110

Grand Total All Awards = $654,110

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Endothelial Enhancer of Zeste Homolog 2 in Cerebral Amyloid Angiopathy and Alzheimer's disease

Award Number: R01AG094006

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2030

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