# Project 1: Brain Pericytes and the Progression of Alzheimer's Disease

> **NIH NIH P20** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $243,962

## Abstract

Alzheimer's Diseases—the most common cause of dementia in aging adults—is a slow, but progressive, 
deterioration of the brain that leads to neurodegeneration and cognitive impairment. The classic 
neuropathological sign of the disease is the accumulation of amyloid-β-containing plaques, which can lead to 
neuronal damage when free amyloid-β oligomers form Ca2+-permeable pores, cause membrane 
permeabilization and neuronal cell death. More recently, cardiovascular pathologies have been implicated in 
the progression of Alzheimer's Disease and other forms of dementia. However, how these pathologies 
contribute to the pathogenesis of Alzheimer's Disease is poorly understood; how vascular dysfunction 
potentiates the failure to clear toxic amyloid-β from ageing brains. Our recent work provides evidence that 
capillaries—the smallest vascular conduits and the point of nutrient delivery and waste removal between blood 
and surrounding neurons —act as a sensory network that detects and responds to neural activity by promoting 
an increase in local blood flow (functional hyperemia). In addition, we observe that contractile pericytes 
maintain the efficiency of network perfusion by controlling blood flow at capillary junctions. In Preliminary 
Results, we provide new evidence that amyloid-β peptide, the major constituent of amyloid plaques in the 
brains of Alzheimer's patients, increases the frequency of Ca2+ events in contractile pericytes, but not in nearby 
vascular smooth muscle cells. This has led us to speculate that amyloid-β peptide-mediated increases in the 
frequency of Ca2+ events interrupt normal pericyte Ca2+ signaling, leading to Ca2+ overload and cell death, and 
disruption of pericyte-mediated control of junctional blood flow. With the support of this COBRE application, we 
propose to test our overarching hypothesis that the progressive loss of pericyte function at capillary junctions 
reduces the efficiency of capillary network perfusion, ultimately affecting the health and function of surrounding 
neurons. The aims of the current study are 1) to elucidate the molecular mechanisms underlying amyloid-β 
peptide-induced increases in pericyte Ca2+ events; and 2) to elucidate the pathophysiological effects of 
amyloid-β on junctional pericyte control of local and global blood flow. Successful completion of these studies 
is expected to provide insights into how amyloid-β peptide accumulation disrupts blood flow within the 
microenvironment to negatively impact neuronal vitality, and to provide therapeutic targets for the prevention of 
the neurodegeneration that leads to cognitive impairment and dementia.

## Key facts

- **NIH application ID:** 9854162
- **Project number:** 1P20GM135007-01
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Albert Louis Gonzales
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $243,962
- **Award type:** 1
- **Project period:** 2020-08-06 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854162

## Citation

> US National Institutes of Health, RePORTER application 9854162, Project 1: Brain Pericytes and the Progression of Alzheimer's Disease (1P20GM135007-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9854162. Licensed CC0.

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