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Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease

Award Number: R01AG074289
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease - PROJECT SUMMARY Alzheimer`s disease (AD) is a progressive degenerative disease of the brain, a dementing illness associated with early neurovascular changes and the accumulation of misfolded amyloid-β (Aβ) and tau in the brain. At present, no effective treatment is available to slow or halt the progression of AD. Hence, uncovering novel mechanisms that govern AD pathogenesis may advance the development of more effective therapeutic strategies to treat this devastating disease. Mounting evidence suggests that the accumulation and aggregation of Ab in brain parenchyma and cerebral blood vessels (CBVs) is a key event leading to other AD-related pathologies. Kinetic studies in patients with sporadic AD indicate that faulty Aβ clearance, rather than Aβ overproduction, is critical for accumulation and aggregation of Aβ in brain. However, the molecular underpinnings of such Aβ accumulation remain poorly understood. Our preliminary studies indicate that heparan sulfate (HS), a type of sulfated polysaccharide that critically mediates cell-cell and cell-matrix interaction and signaling, is strongly reduced in CBVs of AD patients. In this application, we will test our novel hypothesis that HS expressed in CBVs normally facilitates the clearance of Ab out of the brain and that such function is disrupted in AD, leading to impaired Ab clearance. Mechanistically, we hypothesize that HS maintains CBV integrity, functions as a co-receptor in LRP1-mediated Ab clearance and facilitates perivascular Ab elimination. We will pursue the following 3 specific aims to rigorously test our hypothesis: 1. Elucidate the roles of brain endothelial cell (bEC) HS in Ab clearance and test the hypothesis that increasing bEC-HS expression normalizes Ab clearance to mitigate AD pathogenesis. 2. Delineate the molecular mechanisms underlying the roles of bEC-HS in brain Ab clearance and AD pathogenesis. 3. Elucidate the roles of brain vascular smooth muscle cell (bVSMC)- HS in brain Ab clearance and AD pathogenesis. These proposed studies exploit both novel and established genetic, cellular, scRNA-seq and biochemical approaches in conjunction with human AD specimen and AD mouse models. The results of this study are expected to illuminate HS expressed in CBVs serves as a key molecule to mediate brain Ab clearance and decreased CVS-HS expression exacerbates AD, and will provide in vivo evidence for the proof of principle that increasing bEC-HS is an effective intervention to mitigate AD pathogenesis.


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: 2025 ( Subtotal = $587,928 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	3	7/29/2025	NON-COMPETING CONTINUATION	$587,928
														Subtotal = $587,928

Issue Date FY: 2024 ( Subtotal = $599,927 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	7/31/2024	EXTENSION WITH OR WITHOUT FUNDS	$599,927
														Subtotal = $599,927

Grand Total All Awards = $1,187,855

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Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease

Award Number: R01AG074289

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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