# Hypoperfusion, Hemodynamic Control Domains and Neurovascular Dysregulation in AD brain pathology

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $461,400

## Abstract

Alzheimer’s Disease [AD] is a progressive degenerative disorder of unclear etiology and disease-modifying
treatments remain elusive. Abnormal neurovascular regulation can lead to reduced substrate supply to brain,
including capillary and small vessel pericyte regulation with neuronal activity, conduction from small vessels to
larger scale vessels, and hemodynamic responses to neuronal activity. Neurovascular regulation mechanisms
in the context of the aging brain can be differentiated from the premature aging and progressive
neurodegeneration associated with AD and dementia syndrome. Early pathological neurovascular and
metabolic alterations can reduce substrate delivery to the AD brain. Though brain metabolism is altered during
aging, AD demonstrates more severe and premature metabolic insufficiency in comparison to age-matched
controls, attributable to neurovascular dysregulation at multiple levels.
We will analyze mechanisms of neurovascular regulation occurring in age-matched control genotypes (both
wildtype C57Bl/6 and mNOS2-/-) compared to the progressive degeneration noted in the CVN-AD animal
model of Alzheimer’s disease (APPSwDI +/+ mNos2−/−). This unique mouse model closely mirrors human
phenotypic changes, particularly amyloid plaques around blood vessels, phosphorylated tau, and severe
neurodegeneration. Our hypothesis is that degeneration, as noted in both human AD and the relevant CVN-AD
animal model, is worsened by premature aging changes in substrate supply at the capillary, pericyte,
conduction, and hemodynamic levels. Metabolic insufficiency can arise particularly from abnormal
neurovascular coupling and conduction from small to larger vessels, blunting the hemodynamic response to
dynamic neuronal activity. The CVN-AD model mirrors human AD phenotypes with a predictable time course of
behavioral, vascular and circuit degeneration in relation to aging changes hence provides an appropriate pre-
clinical, translational model for analyzing these concepts. We will study novel approaches to evaluating
mechanisms of neurovascular regulation including chemogenetic approaches at the pericyte, mural wall cell
level, assessing activity and conduction to larger capacity cerebral vessels, neurovascular coupling and
hemodynamic responses, to understand dynamic mechanisms of hypoperfusion at critical times of substrate
need, in both hippocampus and neocortex as a function of genotype, gender, and age.

## Key facts

- **NIH application ID:** 10837110
- **Project number:** 5R01AG081774-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** DENNIS Alan TURNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,400
- **Award type:** 5
- **Project period:** 2023-05-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837110

## Citation

> US National Institutes of Health, RePORTER application 10837110, Hypoperfusion, Hemodynamic Control Domains and Neurovascular Dysregulation in AD brain pathology (5R01AG081774-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10837110. Licensed CC0.

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