Sunday, December 7, 2025 12/7/2025

Metabolic and Vascular Factors in tau pathogenesis

Award Number: R01AG066212
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

Group Awards By:

View Award Description

Metabolic and Vascular Factors in tau pathogenesis - ABSTRACT This revised proposal utilizes our recently described novel model of Mixed Dementia (MxD) (Denver et al. 2019), the most prevalent dementia, yet MxD subjects are often excluded from AD trials. There is a paucity of models with coexisting vascular and Alzheimer's (AD) pathologies, in addition to a lack of consensus in neuropathological (or neuropsychiatric) diagnostic criteria for MxD. Therefore, this proposal seeks to identify synergistic and independent interactions between AD and hypertension-associated cerebrovascular disease factors in pathology, behavior and biomarkers and modulation by treatment, sex and ApoE isotype. The SHR- Stroke prone (SHRSP) rat is the most widely studied model for vascular cognitive impairment (VCI) and develop vascular pathology and a compromised neurovascular unit. We used this to create “SHRSPFAD” rats by breeding in mutant APP/PS1 transgenes. Our SHRSPFAD rat shows multiple features of MxD including tauopathy, recently speculated to be increased disproportionately to amyloid in MxD. We propose four aims, which include methods to address limitations of one of the controls: normotensive WKY rats (founder of SHRSP), which is used as the non-hypertensive control, but poses the same limitations as AD models with homozygous colonies (e.g. ApoETR, 3xTg mice etc.), so the aims attempt to overcome this limitations, such as exploring how severity of hypertension affects the synergism between AD and hypertension within phenotype. Aim 1 determines if further increasing hypertension, using high salt diet, used with SHSRP to exacerbate hypertension (and lower VEGF and VGF) affects aging or sex modulation of synergism between AD and hypertension. Aim 2 also addresses this limitation, by reducing hypertension with Angiotensin II Receptor Blockers (ARBs), known to protect the BBB and reduce dementia risk. Thus Aim 2 validates hypertensive-dependent effects on pathology, biomarkers and behavior using ARBs in the SHRSPFAD model. Aims 3 and 4 address effects of ApoE4 the main genetic AD risk factor (notably in women), also impactsing vasculature. Hypertension in post- menopausal female E4 carriers creates a high dementia risk unlike rodents that lack a precipitous drop in antihypertensive and neuroprotective estrogen. Therefore Aim 3: characterizes a novel ApoE SHRSPFAD model and determines the impact of losartan and the anti-estrogen receptors involved in BP control. Since comorbidities in MxD introduce multiple pathways, polypharmacy is necessary in the clinic. Disruption of VEGF signaling is seen in VCI and with ApoE4, so we evaluate the effects of ARB with the FDA approved PPD3 inhibitor Cilostazol, which restores VEGF signaling, protecting the neurovascular unit. Thus, Aim 4 determines efficacy of the combination therapy ARB and Cilostazol. Aims 1-4 variables: vascular- dependent and cognitive variables, bulk and glia- and endothelial-specific RNAseq analysis, tau, Aβ, demyelination, mitochondrial deficits and brain- derived exosomal plasma biomarkers associated with neuroinflammation and disruption of the perivascular unit.


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 = -$206,022 )
2026	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	-$206,022
														Subtotal = -$206,022

Issue Date FY: 2024 ( Subtotal = $681,088 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	5	6/4/2024	NON-COMPETING CONTINUATION	$681,088
														Subtotal = $681,088

Issue Date FY: 2023 ( Subtotal = $677,968 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	4	6/12/2023	NON-COMPETING CONTINUATION	$677,968
														Subtotal = $677,968

Issue Date FY: 2022 ( Subtotal = $683,442 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	3	4/28/2022	NON-COMPETING CONTINUATION	$683,442
														Subtotal = $683,442

Issue Date FY: 2021 ( Subtotal = $677,968 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Aging Research	000	2	5/28/2021	NON-COMPETING CONTINUATION	$677,968
														Subtotal = $677,968

Issue Date FY: 2020 ( Subtotal = $677,968 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Aging Research	000	1	9/11/2020	NEW	$677,968
														Subtotal = $677,968

Grand Total All Awards = $3,192,412

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Metabolic and Vascular Factors in tau pathogenesis

Award Number: R01AG066212

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer