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Transcriptional control of microglia diversification and inflammation

Award Number: RF1NS106721
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Transcriptional control of microglia diversification and inflammation - Project Summary Our proposal focuses on the epigenetic mechanisms of microglia-mediated neuroprotection. We identified the transcription factor PU.1 as an integrator of pro- and anti-inflammatory responses in microglia. We found that during Alzheimer's Disease (AD) in mice and humans, a subpopulation of microglia engaged in the response to amyloid plaques up-regulates genes that are normally expressed in lymphocytes and encode potent regulators of lymphocyte signaling. This transcriptional shift towards the lymphoid lineage correlates with the low expression of PU.1 compared to the rest of the microglia in the AD-affected brain. The regulatory potential of low PU.1 expression was further underscored by the neuroprotective effect of engineered PU.1low microglia in vivo. In our proposal, we will address the mechanisms of the PU.1low microglia-mediated neuroprotection. Our preliminary data suggest that PU.1 downregulation and lymphoid gene expression, and in particular the expression of the surface receptor CD28, enable PU.1low microglia to operate as suppressors of brain inflammatory responses driven by other microglia or by lymphocytes activated during AD. Understanding of the role of microglia- expressed lymphoid proteins in the microglia-driven neuroprotection may offer opportunities for targeted suppression of AD-associated inflammation by engaging the surface-expressed lymphoid proteins in microglia. The link between low PU.1 expression levels and reduced risk of AD in humans underscores the clinical relevance of our studies for human diseases. Another aspect of our proposal deals with microglia-mediated neuroprotection by clearance of the toxic β- amyloid. While studying the transcriptional control of microglia activity, we have discovered a novel role of the bromodomain-containing protein BRD2 in clearance of β-amyloid. We found that BRD2 acts as a nuclear receptor for the protein LC3, that guides critical cellular pathways including autophagy, phagocytosis, endocytosis, and pinocytosis. Intracellular vesicle dynamics mediated by LC3 and LC3-related proteins is essential for maintaining cellular homeostasis and preventing pathological protein accumulation. We showed that BRD2-deficiency and associated increase in LC3-driven autophagy are linked to an increased efficacy of the microglia-driven β-amyloid clearance. This finding reveals a novel mechanism of β-amyloid clearance by microglia and points to BRD2 and its LC3 association as potential key regulatory elements in brain protection against Alzheimer's disease. Targeting of BRD2 or BRD2 interaction with LC3 may create new treatment paradigms for neurodegenerative diseases by enhancing the brain's endogenous capacity to clear pathological aggregates.


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 = $2,010,085 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/4/2026	COMPETING CONTINUATION	$2,010,085
														Subtotal = $2,010,085

Grand Total All Awards = $2,010,085

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Transcriptional control of microglia diversification and inflammation

Award Number: RF1NS106721

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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