# Neurodegeneration and Microvascular Damage in Alzheimer's Disease

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $390,000

## Abstract

Project Summary/Abstract
AD and vascular dementia have been traditionally considered separate pathologies; however, recent data
suggest that there is an additive or synergistic effect of cerebrovascular damage and AD pathology on
cognitive function. The contribution of cerebrovascular change on AD pathogenesis and progression is an
understudied area. Studies of human autopsy brains have shown that the severity of cerebrovascular disease
is correlated with dementia, most often dementia attributed to AD. However, the underlying mechanism is not
clearly understood, and whether cerebrovascular damage is a causal factor in AD pathogenesis or a
consequence of AD progression is not known. Understanding the interaction between the pathogenesis of AD
and the pathogenesis of cerebrovascular damage may lead to the development of new therapeutics that can
target both. Only over the last ten years, however, have we learned that the same signal molecules, e.g.,
VEGF and BDNF, influence the growth of neuronal and vascular networks. PKCε activates the mRNA-
stabilizing protein Hu, which enhances expression of VEGF and BDNF. A decrease in PKCε occurs in neurons
and vascular endothelial cells in aged, AD, and in ischemic brains. We hypothesize that AD pathology results
from a combination of neurologic and cardiovascular factors. In Aim 1, we will pathogenesis in neurons and
microvasculatures in the human AD and aged-matched control hippocampi from subjects with mixed lesions of
hypertension, cardiac disease, and/or cerebrovascular disease. This will provide a thorough understanding of
pathogenesis in MV structural changes related to neurons. In Aim 2, we will assess the effect of PKCε
activation on early spatial memory defect in transgenic mouse models of AD with and without cerebrovascular
disease. Based on our previous results, we expect to show that cerebrovascular disease and MV changes
accelerate neuron loss and AD pathogenesis that is protected with the PKCε-enhanced VEGF & BDNF
expression. In Aim 3, we will determine the effect of PKCε activation on early spatial memory defect in
transgenic mouse models of AD with hypertensive heart disease. At the end of this aim, we expect to show
that MV change associated with the complex of AD and cardiovascular disease (without cerebrovascular
disease) suppresses VEGF & BDNF is prevented with PKCε-specific activators. Understanding the impact of
cerebrovascular dysfunction on AD pathophysiology may lead to the development of new therapeutics that
addresses both neuronal and vascular pathologies to prevent or slow the progression of the disease to
improve the quality of life of affected or at-risk individuals. Our findings may allow for the earlier diagnosis of
AD using cerebrovascular biomarkers that can identify at-risk individuals. Importantly, our findings will have
broader implications for the treatment of other neurodegenerative diseases and conditions, such as ischemic
stroke and traumatic brain injury, in which ...

## Key facts

- **NIH application ID:** 10128343
- **Project number:** 5R01AG058884-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jarin Hongpaisan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-06-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128343

## Citation

> US National Institutes of Health, RePORTER application 10128343, Neurodegeneration and Microvascular Damage in Alzheimer's Disease (5R01AG058884-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10128343. Licensed CC0.

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