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Microglia targeted interventions in prodromal Alzheimer's disease stage

Award Number: R01AG083941
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Microglia targeted interventions in prodromal Alzheimer's disease stage - Project Summary Genome-wide association studies for late-onset Alzheimer’s disease (LOAD) found that >70% loci are localized to genes that are enriched in microglia, the resident immune cells of the brain. The most significant risk variant for LOAD is apolipoprotein E ε4 (APOE4) and its homozygosity increasing AD risk >15-fold. APOE is predominantly expressed in astrocytes and significantly upregulated in microglia near amyloid plaques and by neurodegenerative environments. While microglia protect against development of AD by clearing toxic cellular debris and compacting amyloid plaques, environmental and genetic factors can cause microglia to enter persistent reactive states in which they escalate disease via excessive inflammation and neurotoxicity. Given the role of microglia in AD pathogenesis, microglia-targeted pharmacological and cell therapeutic interventions may be able to protect against AD progression in selectively vulnerable brain regions such as the entorhinal cortex and hippocampus. In the APPNL-G-F AD mouse model, both regions show amyloidosis, reactive gliosis, and synaptic loss in prodromal stages, especially the entorhinal cortex shows electrophysiological impairment prior to cognitive impairment. Thus, these regions are critical targets for preclinical development of novel therapeutics for prodromal AD. Acute pharmacological inhibition of colony stimulating factor 1 receptor with the brain-penetrant drug PLX5622 has been shown to selectively induce “turnover” of microglia (near complete removal of existing microglia and self-renewal of survived microglia), which rescues abnormal hippocampal activity, promotes brain repair, and ameliorates cognitive deficits in aging, traumatic brain injury, and maternal immune activation models. Replacement of AD risk (proinflammatory or APOE4) microglia with APOE3 neutral or APOE2 protective human iPSC-derived microglia may be a promising microglia-targeted AD therapeutic. Therefore, we hypothesize that electrophysiological, molecular, and cellular dysfunctions in the entorhinal cortex and hippocampus at prodromal disease stages is driven by proinflammatory reactive microglia signatures (Aim 1) and APOE4 genotype microglia (Aim 2). It can potentially be treated in adulthood by pharmacologically forced- turnover of AD microglia (Aim 1) and AD microglia replacement with APOE 33 or 22 microglia-like cells (Aim 3). In Aim 1, we will demonstrate molecular and functional changes in forced turnover of microglia on the entorhinal cortex and hippocampus of prodromal AD mice using neuron-like electronic probes during spatial navigation virtual reality. In Aim 2, we will determine APOE genotype effects of human microglia on vulnerability of the entorhinal and hippocampal neurons in chimeric human/mouse AD model. In Aim 3, we will establish cell replacement therapeutics in adulthood by replacing AD microglia to APOE3 or APOE2 cells in adult mice. The goal of this research is to demonstrate molecular mechanisms by which AD and APOE isoform microglia affect neuronal network and to determine the efficacy by which microglia-targeted pharmacological and human iPSC- based therapeutic strategies protect neurons and memory circuits that are selectively vulnerable in AD patients.


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 = $782,066 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	3	7/15/2025	NON-COMPETING CONTINUATION	$782,066
														Subtotal = $782,066

Issue Date FY: 2024 ( Subtotal = $816,586 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	2	6/10/2024	NON-COMPETING CONTINUATION	$816,586
														Subtotal = $816,586

Issue Date FY: 2023 ( Subtotal = $830,339 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	1	7/18/2023	NEW	$830,339
														Subtotal = $830,339

Grand Total All Awards = $2,428,991

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Microglia targeted interventions in prodromal Alzheimer's disease stage

Award Number: R01AG083941

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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