# Metabolic and Vascular Factors in tau pathogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $677,968

## Abstract

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-
...

## Key facts

- **NIH application ID:** 10058790
- **Project number:** 1R01AG066212-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** SALLY ANN FRAUTSCHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $677,968
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058790

## Citation

> US National Institutes of Health, RePORTER application 10058790, Metabolic and Vascular Factors in tau pathogenesis (1R01AG066212-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058790. Licensed CC0.

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