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Microglial lysosomes and selective neuronal vulnerability

Award Number: R01AG075909
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Microglial lysosomes and selective neuronal vulnerability - 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 regions (Aim 3). These studies will reveal whether these organelles are central orchestrators of microglial phenotype and will identify molecular targets for promoting neuroprotective microglial phenotypes to preserve synaptic function in vulnerable populations of neurons.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $292,584 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	5	1/26/2026	NON-COMPETING CONTINUATION	$292,584
														Subtotal = $292,584

Issue Date FY: 2025 ( Subtotal = $360,074 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	4	3/25/2025	NON-COMPETING CONTINUATION	$297,823
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	002	4	6/18/2025	NON-COMPETING CONTINUATION	$26,472
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	004	4	7/15/2025	SUPPLEMENT FOR EXPANSION	$35,779
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	003	3	7/7/2025	OTHER REVISION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	001	3	6/5/2025	TERMINATION	$0
														Subtotal = $360,074

Issue Date FY: 2024 ( Subtotal = $426,827 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	3	2/21/2024	NON-COMPETING CONTINUATION	$306,860
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	001	3	2/24/2024	SUPPLEMENT FOR EXPANSION	$85,871
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	002	3	6/10/2024	NON-COMPETING CONTINUATION	$34,096
														Subtotal = $426,827

Issue Date FY: 2023 ( Subtotal = $447,410 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	2	1/20/2023	NON-COMPETING CONTINUATION	$397,478
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	001	2	6/27/2023	SUPPLEMENT FOR EXPANSION	$49,932
														Subtotal = $447,410

Issue Date FY: 2022 ( Subtotal = $360,783 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Aging Research	000	1	3/31/2022	NEW	$360,783
														Subtotal = $360,783

Grand Total All Awards = $1,887,678

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Microglial lysosomes and selective neuronal vulnerability

Award Number: R01AG075909

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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