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Investigating ACE1 R1279Q-Induced Vascular Dysfunction and Neuroinflammation in Alzheimer's Disease

Award Number: K01AG095334
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Investigating ACE1 R1279Q-Induced Vascular Dysfunction and Neuroinflammation in Alzheimer's Disease - PROJECT SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that is characterized by progressive and irreversible cognitive impairment. The symptoms of AD are caused by the selective degeneration of neurons responsible for memory and learning. Angiotensin I converting enzyme (ACE1) and the renin-angiotensin system (RAS) function in the vascular system to regulate blood pressure, although they are also expressed in neurons and may have a role in selective vulnerability in AD. Rare protein-altering variants in ACE that are associated with AD risk in humans were recently discovered through whole exome and whole genome sequencing. One rare AD-associated variant in ACE1, R1284Q, was investigated in knockin (KI) mice. KI mice have increased brain ACE1 and have age-related neurodegeneration in the hippocampus, while other brain regions are resistant. Importantly, hippocampal neurodegeneration is prevented by treatment with ACE1 inhibitor (ACEis) and angiotensin II receptor type 1 (AT1R) blocker (ARBs) drugs. ACE1 is increased in sporadic AD brain, suggesting that elevated RAS activity is a common feature of AD. The overall hypothesis of this study is that ACE1 R1284Q exacerbates neurodegeneration by aberrantly increasing angII-AT1R signaling within the neurovascular unit leading to vascular dysfunction, neuroinflammation, and selective hippocampal neurodegeneration. Aβ and other “second hits” may potentiate the age-induced increase in ACE1/RAS signaling to accelerate selective neurodegeneration. However, ACE1 and AT1R are expressed in multiple cell types and brain regions, and the mechanisms responsible for ACE1-associated hippocampal neurodegeneration are unclear. Single-cell RNA sequencing will be used to determine the pathways and cell types involved in vascular dysfunction (Aim 1) and neuroinflammation (Aim 2) and their connection to ACE1 KI-mediated neurodegeneration. Cell-cell phenotypes and regional differences in ACE1 KI mice will be uncovered using innovative cutting-edge spatial RNA sequencing (Aim 3). Through these aims, Dr. Cuddy will accomplish her short-term career enhancement goals: 1) gain specialized training in sc/spRNAseq and bioinformatic analyses and 2) acquire cerebrovascular research techniques. Dr. Cuddy will work with a team of mentors at Northwestern University with complementary expertise to accomplish these aims. She will receive intensive mentored career training and participate in professional development courses and workshops at Northwestern University. Together, this will enable Dr. Cuddy to achieve her long-term goal of establishing an independent translational research program using transcriptomic approaches, mouse models and iPSCs to understand the role of ACE1 in the brain and how changes in ACE1 function mediate AD risk at the molecular level. This will provide insight into understanding ACE1 in sporadic AD patients and whether ACEis or ARBs could be repositioned for the treatment of 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 = $124,987 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Aging Research	000	1	7/1/2026	NEW	$124,987
														Subtotal = $124,987

Grand Total All Awards = $124,987

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Investigating ACE1 R1279Q-Induced Vascular Dysfunction and Neuroinflammation in Alzheimer's Disease

Award Number: K01AG095334

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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