# Astrocyte and microglial cell state transitions in response to activation of the immune system in Alzheimer's disease

> **NIH NIH U01** · INSTITUTE FOR SYSTEMS BIOLOGY · 2020 · $472,750

## Abstract

Project Summary/Abstract
Cell state transitions mediated by epigenetic remodeling and transcriptome reprogramming are fundamental to
many biological processes, including stem cell differentiation, cancer cell adaptive resistance development,
immune cell activation, etc. In our parent U01 grant, we have developed an analytical framework to resolve the
key regulators of the dynamic cell state changes associated with such transitions in cancer through a strategic
orchestration of information-theoretic approaches, time-resolved multi-omics characterization, and single-cell
analytics. Here, we propose to extend this method to analyze the state transition of two important cell types that
play critical roles in the regulation of Alzheimer’s disease (AD) pathology.
Genetic associations with increased risk for AD implicate both innate immune processes and microglial cells,
and suggest that environmental factors, such as infection, may play a role in AD. Chronic infection of neurotropic
herpesviruses, particularly HSV-1, has been found to contribute to the development of AD pathology. Activation
of astrocytes and microglia upon such chronic infection have both neuroprotective and neurotoxic effects on AD.
Astrocytes and microglia appear to mutually coordinate their activation in a pro-amyloidogenesis feed-forward
loop, where β-amyloid plaques induce astrocyte secretion of C3, followed by a C3aR-dependent reduction of
microglial phagocytosis. Additionally, microglia can also trigger A1 reactive astrocytes by releasing fragmented
mitochondria, or the pro-inflammatory cytokines Il-1α, TNFα and C1q13, resulting in neuronal loss in AD. In a
nutshell, this heterogeneous microenvironment of AD is comprised of a dynamic composition of cell types and
states, reminiscent, in a physical sense, of an evolving tumor microenvironment. The evolving transcriptional
and epigenetic programs lead to functional alterations that contribute to AD pathogenesis. Attention to these
non-neuronal cell types has arisen in attempt to more holistically understand the disease and highlight novel
therapeutic avenues.
Our hypothesis is that time-resolved multi-omics and single-cell characterizations, coupled with information
theory approaches that can integrate such kinetic data into a single self-consistent model can help resolve AD’s
physiopathology. We propose to leverage the information theory-based analytical framework we have developed
within our parent U01 project as well as a novel neurotropic herpesvirus infection amyloid mouse model to
investigate the dynamic cell state changes of astrocytes and microglia and their interplay in an HSV-1 infection
model of AD pathology. This admin supplement program would allow us to extend our methodologies to address
AD, with two goals. First, we will improve our understanding of the role of microglia and astrocytes in the
regulation of AD pathology. Second, and similar to what we have found in our tumor biology work, we may also
reveal new ave...

## Key facts

- **NIH application ID:** 10123589
- **Project number:** 3U01CA217655-05S1
- **Recipient organization:** INSTITUTE FOR SYSTEMS BIOLOGY
- **Principal Investigator:** James R. Heath
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $472,750
- **Award type:** 3
- **Project period:** 2017-08-08 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123589

## Citation

> US National Institutes of Health, RePORTER application 10123589, Astrocyte and microglial cell state transitions in response to activation of the immune system in Alzheimer's disease (3U01CA217655-05S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10123589. Licensed CC0.

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