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Contribution of a novel OPN-producing CD11c+ microglial subset to AD

Award Number: R01AG075837
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Contribution of a novel OPN-producing CD11c+ microglial subset to AD - Summary We have recently identified a small subset of CD11c+ microglia as the sole producer of OPN (Osteopontin; Spp1) and major disease driver in the 5XFAD mouse model of Alzheimer’s Disease (AD). Our analysis of OPN- producing CD11c+ microglia has divided Disease-Associated Microglia (DAM) that surround Aβ plaques into two opposing subsets that together regulate AD pathology. A pathogenic CD11c+OPN+ microglial subset promotes proinflammatory responses and drives AD development, and a protective CD11c+OPN− microglial subset degrades Aβ fibrils and inhibits disease pathology. We find that genetic deletion of OPN (a) inhibits microglial proinflammatory responses, (b) enhances TREM2/TAM-dependent uptake and lysosomal breakdown of Aβ plaques and (c) markedly improves cognitive function. Analyses of clinically and neuropathologically characterized brain tissue from AD patients and controls (Mt. Sinai Brain Bank and the Rush Alzheimer’s Disease Study) confirm these murine findings. In addition, administration of α-OPN mAb markedly ameliorates the microglial proinflammatory responses and reduces Aβ plaques in 5XFAD mice. Here we propose Osteopontin (OPN) as a novel and tractable target based on preclinical studies of the 5XFAD model of Alzheimer’s disease (AD) (performed at DFCI) and analysis of well-characterized human brain tissue (performed at Mt. Sinai and Rush Alzheimer’s Disease Center) (Aims 1 and 2). We also test the therapeutic impact of mAb-based approaches that target OPN in the 5XFAD mouse model in Aim 3. The overarching goal of our therapeutic approaches is conversion of proinflammatory microglia into a non-inflammatory phenotype with enhanced ability to engulf and digest Aβ fibrils. Identification of a pathogenic (CD11c+OPN+) microglial subset in both murine and human brain tissue provides new insight into the pathogenic pathway that may drive clinical AD and a foundation for the development of therapeutics that target this pathology and halt or reverse disease progression.


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 = $455,377 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	12/6/2024	NON-COMPETING CONTINUATION	$455,377
														Subtotal = $455,377

Issue Date FY: 2024 ( Subtotal = $505,974 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	1	1/16/2024	NEW	$505,974
														Subtotal = $505,974

Grand Total All Awards = $961,351

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Contribution of a novel OPN-producing CD11c+ microglial subset to AD

Award Number: R01AG075837

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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