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Cerebrovascular endothelial cilia in the pathogenesis and therapy of Alzheimer's disease

Award Number: R03AG080418
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Cerebrovascular endothelial cilia in the pathogenesis and therapy of Alzheimer's disease - Primary cilia are microtubule-based organelles, extending from the surface of vascular endothelial cells to sense extracellular signaling cues and fluid-shear stress. Cilia dysfunctions (ciliopathies) have been linked to numerous genetic disorders, and manifest a broad range of symptoms, including hypertension (HTN) and cognitive and memory dysfunction. We demonstrated that the inability of primary endothelial cilia to sense and transmit fluid shear stress can lead to nitric oxide (NO) deficiency and cause vascular HTN. HTN can cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment, contributing to the progression of Alzheimer’s disease (AD). In addition, decreased biosynthesis of NO contributes to CAA in AD patients through increased deposition of beta amyloid (Aβ). However, the molecular mechanisms underlying the pathogenesis of HTN and AD are incompletely understood thereby limiting our ability to prevent initiation and progression of this disease. Recent studies have identified specific mAChR- regulated pathways as novel therapeutic targets for AD. Muscarinic acetylcholine receptors (mAChRs) are also expressed throughout the cardiovascular system and can regulate BP and NO biosynthesis. However, the connection between cilia, mAChR signaling, and HTN in the pathogenesis of AD has never been investigated before. Supported primarily by our recent discovery of the AChM3R localization to primary cilia, we propose a bold idea to look at the pathophysiological roles of cerebrovascular ciliary receptors in BP and in AD in vivo. This application is designed to advance the concept that in early stages of AD, diminished cilia- mediated NO biosynthesis and deposition of endothelium-derived Aβ in cerebral blood vessel wall is an important mechanism contributing to pathogenesis HTN and AD. We generated vascular-specific AChM3R and Tg737 KO mice, in which AChM3R and Tg737 (important for ciliogenesis) were specifically deleted from the vascular endothelia. Interestingly, these mice developed high BP, associated with attenuated NO production, and altered cognitive function. These studies demonstrated the physiological significance of primary cilia-derived NO in the long-term control of vascular and cognitive function. In this proposal, we formulated the hypothesis that endothelial ciliary AChM3R contributes to AD progression through diminished NO biosynthesis. In Aim 1, we will study the effect of AChM3R or cilia deletion from vascular endothelia in 3xTgAD model on Aß accumulation, vascular reactivity, and brain vascular integrity/function. We will also test the effect of novel pharmacological modulators on enhancing ciliary AChM3R-mediated NO biosynthesis. In Aim 2, we will examine the role of cerebrovascular cilia and AChM3R KO in BP and AD manifestations in the 3xTgAD model. We anticipate that successful completion of this project will offer new opportunities to utilize endothelial mAChRs as molecular targets for therapeutic interventions designed to prevent detrimental effects of HTN on cerebrovascular and cognitive function.


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 = $0 )
2026	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Aging Research	000	2	3/31/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $151,775 )
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Aging Research	001	2	6/21/2024	NON-COMPETING CONTINUATION	$15,177
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Aging Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$136,598
														Subtotal = $151,775

Issue Date FY: 2023 ( Subtotal = $149,050 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Aging Research	000	1	1/31/2023	NEW	$149,050
														Subtotal = $149,050

Grand Total All Awards = $300,825

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Cerebrovascular endothelial cilia in the pathogenesis and therapy of Alzheimer's disease

Award Number: R03AG080418

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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