Tuesday, July 1, 2025 7/1/2025

Crosstalk between innate-immunity human microglia and adaptive-immunity Tregs in Alzheimer's disease

Award Number: R01AG078756
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Crosstalk between innate-immunity human microglia and adaptive-immunity Tregs in Alzheimer's disease - Title: Crosstalk between innate-immunity human microglia and adaptive-immunity Tregs in Alzheimer’s disease (RFA-AG-22-017) Project Summary This application is in response to RFA-AG-22-017, looking at crosstalk between innate and acquired immunity in Alzheimer’s disease (AD). AD affects ~5% of people over age 65, and its prevalence is increasing. Neuroinflammation has been described in neurodegenerative disorders, and particularly in AD. Microglial cells, the resident macrophages of the central nervous system (CNS), respond to different pro- inflammatory stimuli by releasing glutamate, as well as pro-inflammatory cytokines and chemokines. Glutamate release from astrocytes and microglia has also been observed after exposure to Aβ and to αSyn, proteins that are misfolded in AD. T lymphocytes, express several NMDA-type glutamate receptors (NMDARs), and we have also detected their expression in Tregs, whose activity can reportedly ameliorate neurodegenerative disorders. Using patch-clamp recording, our Preliminary Studies show for the first time the presence of functional NMDAR-operated ion channels on human Tregs. Glutamate is known to affect T cell migration and activation; however, the effect of glutamate on Treg migration/activation has not been reported, and, specifically, it is not known how this might impact neurons in AD brain. We hypothesize that glutamate exposure of Tregs will limit their release of anti-inflammatory and neuroprotective factors, thus contributing to neuronal synaptic damage and cell loss. This crosstalk between the innate and acquired immune system may represent a significant contributor to the pathogenesis of AD. We have recently developed a protocol for generating human iPSC-derived microglia (hiMG) following a yolk sac differentiation method (brain microglia originate from the yolk sac and not from the bone marrow). We will test our hypothesis using a platform of hiPSC-derived microglia (hiMG), human Tregs (isolated from normal blood donors), and hiPSC-derived cerebrocortical neurons (hiN) bearing AD mutations (vs. their isogenic/gene- corrected controls). Using this platform, we show in our Preliminary Studies that hiMG release glutamate following activation with oligomeric Aβ and αSyn. We will systematically investigate the mechanism of the activation of Tregs by glutamate released by hiMG, and the effect of this cellular crosstalk on neuronal function. We will evaluate neuronal synaptic integrity and function as well as neuronal survival. The knowledge gained from this study will shed light on the effect of glutamate on neuroinflammation in a human context, and will provide insight into the effect of crosstalk between human microglial and Tregs in stimulating Treg activation. Thus, the work may aid in the development of future novel therapeutic interventions based on human microglial and Treg function and interaction.


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: 2025 ( Subtotal = $450,800 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	4/28/2025	NON-COMPETING CONTINUATION	$414,000
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	4	6/20/2025	NON-COMPETING CONTINUATION	$36,800
														Subtotal = $450,800

Issue Date FY: 2024 ( Subtotal = $460,000 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	6/12/2024	NON-COMPETING CONTINUATION	$460,000
														Subtotal = $460,000

Issue Date FY: 2023 ( Subtotal = $452,500 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	5/18/2023	NON-COMPETING CONTINUATION	$452,500
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	2	9/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $452,500

Issue Date FY: 2022 ( Subtotal = $443,750 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	8/19/2022	NEW	$443,750
														Subtotal = $443,750

Grand Total All Awards = $1,807,050

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Crosstalk between innate-immunity human microglia and adaptive-immunity Tregs in Alzheimer's disease

Award Number: R01AG078756

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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