# The role of astrocytes in Alzheimer's disease pathogenesis

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $459,185

## Abstract

Astrocytes are the most abundant cells in the central nervous system, however their role in health and
disease remains a mystery. Astrocytes are very heterogeneous in structure and molecular profile. A single
astrocyte creates a distinct non-overlapping territory that encompasses thousands of synapses. Their
extensive branches and fine processes allow direct communication over long distances, as well as indirect
communication through secretion of chemokines and cytokines. Astrocytes are also a significant
component of the neurovascular unit as their endfeet processes terminate directly onto cerebral vessels,
regulating cerebral blood flow according to metabolic demand. While in vitro models, including primary
astrocytes and acute brain slices, have provided great insight into the physiology of astrocytes in health
and disease scenarios, it is clear these preparations devoid of the complexity of the role of astrocytes in
vivo. Thus, efforts to study astrocyte physiology should be directed as much as possible to the most
physiologically relevant system: the intact living brain. We and others have demonstrated through in vivo
imaging of intracellular calcium that astrocytes are dynamic players in the brain, and that the progression of
Alzheimer's disease pathology alters their morphology and signaling characteristics. More specifically, we
determined that in the presence of senile plaques, astrocytes in the brain have elevated intracellular
calcium, exhibit hyperactive signaling, and can initiate spontaneous calcium waves. This allows astrocytes
to respond to focal pathological insults with both focal and long range responses. These observations
demonstrated that astrocytes respond to amyloid deposition with a change in function, but left several
fundamental questions unanswered. Here, we wish to extend our previous observations and determine
what the contribution of the altered calcium signaling is to the degenerative process that occurs in AD. The
use of genetically encoded indicators, specifically expressed in astrocytes, along with in-vivo imaging will
allow us to explore the effect of amyloid on astrocyte structure and function at the synapse and the
neurovascular unit. We will also determine if the alterations depend on senile plaque deposition, or soluble
oligomeric Aβ and whether the alterations are beneficial or detrimental to brain function. We propose
experiments where astrocyte specific increases or decreases in calcium signaling will be evaluated in
healthy and diseased brains. Finally, we will ask how clinically relevant manipulation of the amyloid
cascade will affect calcium signaling in astrocytes and the degenerative process. These experiments will
shed light on the role of astrocytes in the healthy and diseased brain, and will lead to new targets for
therapeutic manipulation in Alzheimer's disease.

## Key facts

- **NIH application ID:** 9880375
- **Project number:** 5R01AG054598-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Brian J Bacskai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $459,185
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880375

## Citation

> US National Institutes of Health, RePORTER application 9880375, The role of astrocytes in Alzheimer's disease pathogenesis (5R01AG054598-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880375. Licensed CC0.

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