# Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

Vascular dementia (VaD) is often caused by small vessel arteriosclerotic disease, resulting in ischemic
damage to white matter and associated neurodegeneration. Autopsy studies indicate that such changes
contribute to the roughly one-third of dementia cases attributed to mixed pathology (MxD), with features of both
Alzheimer's disease (AD) and VaD. MxD is particularly prevalent among older Veterans, who have increased
risk factors such as metabolic syndrome and cardiovascular disease. However, current clinical trials with AD
therapeutics frequently exclude patients with MxD. The interactions of vascular and AD pathology remain
elusive, in part due to the dearth of animal models that recapitulate MxD symptomology and pathology. Our
project addresses this hurdle, establishing a novel rat model of MxD to elucidate mechanisms associated with
vascular complications in AD. We examine the impact of promising therapeutics to prevent AD in the MxD
model, focusing on amyloid vaccines, to facilitate the development of combination therapies that can minimize
adverse effects of vaccine in MxD patients, such as vasogenic edema and microbleeds. Although
asymptomatic in patients with pure AD, the impact on AD patients with VaD is unknown. This proposal will
assess: a) if VaD exacerbates AD-associated Aβ and/or tau pathology; b) differences in peripheral and central
inflammation in VaD, AD, and MxD relative to cognitive and/or neurodegenerative parameters; c) whether
plasma endothelial microparticles differentiate VaD, AD, and MxD; and d) the effects of known modifiers of AD
pathology on MxD. This proposal uses an APP/PS1 transgenic rat model of AD, which develops age-related
cognitive deficits, Aβ/tau deposition, and gliosis. In Aim 1, we examine the impact of this FAD transgene in
spontaneously hypertensive stroke-prone (SHR-SP) rats, which exhibits age-related vascular and white matter
pathology, neuron loss and progressive cognitive deficits. This MxD model (SHR-FAD) is compared with FAD
positive controls and nonTg rats [SHR-SP versus the control strain WKY] for differences in cognition;
peripheral and central inflammation, vascular and parenchymal Aβ, and synaptic loss; and other AD- and VaD-
associated pathologies. Plasma and CSF biomarkers corresponding to specific disease pathologies will be
identified. Aim 2 investigates interventions that promote amyloid clearance: passive immunization with an anti-
Aβ antibody and curcumin, a pleiotropic Aβ-binding molecule, to determine their effects on vascular Aβ
deposition and cerebrovascular disease in the SHR-FAD model of MxD. We hypothesize that VaD exacerbates
neuroinflammation, synaptic loss and tau accumulation, but reduces neuritic plaques, increasing
cerebrovascular amyloid deposition. Increased cerebral penetration of the peripheral anti-Aβ antibodies and
increased plasma levels of cerebrovascular microparticles and cellular adhesion molecules may parallel
disruption of the blood brain barrier. Completion ...

## Key facts

- **NIH application ID:** 9867518
- **Project number:** 5I01BX003485-04
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** SALLY ANN FRAUTSCHY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867518

## Citation

> US National Institutes of Health, RePORTER application 9867518, Neuroinflammation and Neurodegeneration in a Transgenic Alzheimer Rat with Vascular Disease (5I01BX003485-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9867518. Licensed CC0.

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