# Astrocytes as governing pathological drivers of neurovascular dysfunction in AD

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $511,105

## Abstract

Astrocytes as governing pathological drivers of neurovascular dysfunction in AD
Abstract:
Alzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disease, characterized by
cognitive decline. The pathogenesis of AD is complex, and the etiology has yet to be fully elucidated. The
pathological manifestations of AD involve amyloid (Abeta) plaques and neurofibrillary tangles (NFTs), as well
as a significant synaptic loss and neuronal degeneration, and a neuroinflammatory process accompanied by
microglial and astrocytic activation. Specifically, the role of astrocytes in AD is very limited, although their
contribution is likely crucial in the initiation and progression of AD. Astrocytes undertake numerous
fundamental functions for the general homeostasis of the central nervous system, maintaining normal brain
activities, and are key players in aging and dementia. Astrocytes are vital for maintaining the health of the
neurovascular unit such as (but not limited to): contributing to synaptic transmission, blood flow dynamics,
neurovascular coupling, glutamate homeostasis, potassium homeostasis, osmotic regulation, removal of
interstitial waste products from the parenchyma, contributing to blood-brain barrier (BBB) function, sleep health
and wakefulness. Astrocytes play an important role in functional hyperemia, in which local increases in blood
flow meet the metabolic demands of increased neuronal activity. These findings highlight astrocytes as a
central player within the neurovascular unit. Astrocytes demonstrate functional activity through calcium
signaling, however, the role of astrocytic calcium signaling pathophysiology in neurovascular unit dysfunction
remains poorly understood. We will test our governing hypothesis that astrocytic calcium signaling
pathophysiology is a major governing pathological driver of neurovascular unit dysfunction in AD and
an exciting and novel disease modifying therapeutic target. We have powerful in vivo tools and expertise
to thoroughly test this hypothesis in vivo with multiphoton microscopy. We will image calcium concentrations
and dynamics using genetically encoded calcium reporters targeted to astrocytes or neurons in all of the
cellular compartments within single astrocytes, along with amyloid deposits, the vasculature, and neuronal
calcium signaling to identify the mechanism of the astrocyte pathophysiology observed in mouse models of
AD. We will interrogate the system through observations of plaque proximity, test the direct role of soluble
Abeta oligomers, and use a functional hyperemia approach based on a visual stimulation paradigm to evaluate
the deterioration of the function of the complete neurovascular unit. These experiments in total will determine
which components of the neurovascular unit are compromised and when over the lifetime of the mice.
Ultimately, this will guide decisions for the development of novel therapeutic approaches in AD.

## Key facts

- **NIH application ID:** 10767320
- **Project number:** 5R01AG054598-07
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Brian J Bacskai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $511,105
- **Award type:** 5
- **Project period:** 2017-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767320

## Citation

> US National Institutes of Health, RePORTER application 10767320, Astrocytes as governing pathological drivers of neurovascular dysfunction in AD (5R01AG054598-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10767320. Licensed CC0.

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