# Imaging the metabolic and phagocytic landscape of microglia in Alzheimer’s disease

> **NIH NIH R03** · STANFORD UNIVERSITY · 2021 · $157,525

## Abstract

Imaging the Metabolic and Phagocytic Landscape of Microglia in Alzheimer’s Disease
Genome-wide association studies show that some of the strongest genetic risk variants for Alzheimer’s disease
(AD) involve genes exclusively expressed in microglia, indicating its central role in AD pathology. Microglia are
the resident immune cells of the brain, essential for maintaining the health and function of the brain, as well as
providing a first line of defense by phagocytizing debris and secreting cytokines. In AD, characterized by a CNS
environment with chronic exposure to cellular debris and protein aggregation, recent single-cell RNA sequencing
has uncovered a variety of microglial transcriptional states specific to AD, indicating both protective and
detrimental functions. While their transcriptional profiles are well-characterized, we lack an understanding of the
molecular mechanisms that drive the formation of protective/detrimental microglial phenotypes, their functional
characteristics and how they inform AD disease pathology. Only by connecting transcriptional profiles to
functional cell-states can we identify promising, new therapeutic targets. Subpopulations with detrimental
functional signatures may represent novel therapeutic targets for AD. This requires the integration of new
technologies into the field, where the transcriptional profile of individual cells can be complemented by their
functional signatures and correlated with microglia-activating agents and pathological hallmarks.
 Here, we propose to complement available transcriptional data with microscopy of the metabolic and
phagocytic landscape of microglia in the human AD brain. The heterogeneity of microglial transcription
makes it difficult to unambiguously distinguish phenotypes based on immunostaining in conventional
fluorescence microscopy. Instead, we have developed a front-line nonlinear microscopy platform, where
microglial phenotypes can be distinguished based on their metabolic and phagocytic profiles using spectral
coherent anti-Stokes Raman (CARS) and simultaneous two-photon excited fluorescence (TPEF)
microscopy. The profiles will be compiled from quantitative data extracted from the microscopy images;
amounts of (i) intracellular lipid stores, (ii) mitochondria, and (iii) the cellular redox ratio will be integrated into the
metabolic profile, while (iv) lysosomal myelin/amyloid debris, (v) cytosolic myelin debris, and (vi) accumulating
undegradable waste as lipofuscin will form the phagocytic profile. By further integrating a capability to map the
distribution of specific RNA transcripts using RNA probes (RNAScope), we will be able to link
transcriptional expression to the metabolic and phagocytic profiles at the single cell level. Specifically,
we will investigate the metabolic and phagocytic signatures of microglia in human AD brain tissues that express
a set of genes, which we have discovered to modulate lipid accumulation in human immune cells through our
functional ...

## Key facts

- **NIH application ID:** 10190479
- **Project number:** 1R03AG071791-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Sarah C Heilshorn
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,525
- **Award type:** 1
- **Project period:** 2021-04-15 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190479

## Citation

> US National Institutes of Health, RePORTER application 10190479, Imaging the metabolic and phagocytic landscape of microglia in Alzheimer’s disease (1R03AG071791-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10190479. Licensed CC0.

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