# Microglial lysosomes and selective neuronal vulnerability

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $397,478

## Abstract

Project Summary / Abstract
The overall goal of this proposal is to reveal central regulators of microglial attributes that can impact
synapses. Synaptic dysfunction is tightly linked to declining cognition and neuronal health during aging. A long-
standing mystery in neuroscience is why some CNS neurons are more vulnerable to age-associated synapse
loss and neurodegenerative disease. Microglia are well-positioned to influence synapses throughout the
lifespan, being equipped to induce synapse formation, synapse elimination and alter synapse composition
through multiple mechanisms. Moreover, synapse-relevant attributes of microglia change during aging,
including their cell process motility, phagocytic behaviors, and production of inflammatory factors. We and
others recently discovered that microglia exhibit region-specific phenotypes, raising the possibility that
microglial regulation of synaptic health varies. In addition, our preliminary data indicate that ventral tegmental
area (VTA) and substantia nigra pars compacta (SNc) microglia begin to proliferate and produce inflammatory
factors during midlife in mice, and months before microglia in other basal ganglia nuclei. These “pockets” of
early inflammation are likely detrimental to synaptic function of nearby dopamine neurons, which are highly
vulnerable to functional decline and degenerative disease during aging. Here, we will investigate the possibility
that microglial lysosomes can simultaneously regulate multiple synapse-relevant attributes of these cells, and
that regional differences in lysosome function give rise to regional variation in microglial aging and synapse
vulnerability. Lysosomes are typically viewed as purely degradative organelles, but new data show that they
are intimately involved in membrane recycling and intracellular signaling that can shape cell properties. Indeed,
lysosomes play a central role in regulating macrophage phenotype, including their inflammatory profiles,
phagocytosis, and responses to aging. Our findings suggest that lysosomes play similar regulatory roles within
microglia; the region-specific phenotypes and responses to aging that we observe within VTA/SNc microglia
were accompanied by prominent differences in lysosome abundance, expression of lysosome component
genes, and rates of lysosome overload with protein-lipid aggregates, compared to microglia in other basal
ganglia nuclei. Nonetheless, surprising little is known about microglial lysosomes in vivo. Focusing on the basal
ganglia and working in mice, we will use multidisciplinary approaches to define the composition and functional
status of microglial lysosomes across brain regions and lifespan (Aim 1). We developed novel methods to
manipulate microglial lysosome overload and will determine how this shapes synapse-relevant microglial
attributes during aging (Aim 2). Finally, we will directly measure how microglial lysosome overload affects
lifespan synaptic integrity and function in distinct brain re...

## Key facts

- **NIH application ID:** 10599106
- **Project number:** 5R01AG075909-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Lindsay Mitchell De Biase
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $397,478
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599106

## Citation

> US National Institutes of Health, RePORTER application 10599106, Microglial lysosomes and selective neuronal vulnerability (5R01AG075909-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10599106. Licensed CC0.

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