# Changes in cerebrovascular function with aging in normal and AD brain

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2021 · $131,554

## Abstract

The surface of cerebral blood vessels is covered nearly entirely by astrocyte processes called endfeet. Astrocytic
endfeet are perfectly positioned to interact with the endothelial vessel walls, and, where present, the surrounding
smooth muscles or pericytes. Through the release of vasoactive molecules such as PGE2, astrocytes regulate local
blood flow (functional hyperemia) and through the release of angiogenic signals induce tight junction proteins that
form the blood brain barrier (BBB). Consequently, any condition that compromises the structure or function of the
endfoot can cause impaired blood flow or impairments of the BBB. In a previous study using a model of familial
Alzheimer disease (AD; hAPPJ202), we1 showed vascular amyloid deposits aggregating between the astrocytic
endfeet and the vessel wall and such amyloid laden vessels showed an impaired ability to regulate vascular tone
and blood flow upon stimulation. Preliminary data suggests that where amyloid deposits are present on vessels
and endfeet displaced, focal breaches in the BBB occur. However, the causative role of vascular amyloid versus
structural and functional changes of astrocytic endfeet in this context are not known. Indeed, while reduced blood
flow and weakening of the BBB have been demonstrated with aging, the specific role of astrocytes in vessel health
over the lifespan are largely unknown. We hypothesize that normal aging is associated with progressive dysfunction
of astrocytic endfeet causing impairment in functional hyperemia and gradual weakening of the BBB. These agerelated
impairments are accelerated in the AD brain as a function of amyloid being functionally “toxic” to
astrocytes and/or pericytes. Here we propose to use two genetic mouse model of familial AD (hAPPJ202, APP233)
with robust vascular amyloidosis1,4 and progressive gliosis1, and age matched control animals to study the specific
role of astrocytes and pericytes to maintain vessel health and function during normal and pathological aging.
No prior studies have examined specific functional impairments of astrocyte endfeet in normal aging compared to
AD, and a possible specific gliotoxic effect of amyloid; two conceptually innovative ideas. State of the art chronic in
vivo multi-photon imaging will be applied to well established transgenic mouse models of AD with vascular
amyloidosis. Combined with novel cell-type specific genomics and proteomics, this proposal will shed light on
astrocyte specific changes in gene and protein expression over the time course of AD (and normal aging) with specific
analysis of gender differences.

## Key facts

- **NIH application ID:** 10112151
- **Project number:** 5R01AG065836-02
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** HARALD W SONTHEIMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $131,554
- **Award type:** 5
- **Project period:** 2020-03-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112151

## Citation

> US National Institutes of Health, RePORTER application 10112151, Changes in cerebrovascular function with aging in normal and AD brain (5R01AG065836-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112151. Licensed CC0.

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