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Deciphering the role of CX3CR1 in Modulating Mechanisms of Amyloid driven Neurodegeneration in Alzheimer's Disease (Diversity Supplement)

Award Number: RF1AG069425
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The amyloid-cascade hypothesis states that deposition of extracellular Aß plaques is the primary event in AD that facilitates accumulation of hyperphosphorylated tau (pTau), formation of neurofibrillary tangles (NFTs) and drives subsequent neurodegeneration. Microglial activation is the earliest response to pathological changes in the brain and is known to shape neuronal activity and immune activation of neighboring glial cells. Thus, how Aß-driven microglial activation shapes neurodegenerative signaling in AD is a critical unknown in current therapeutic approaches. Communication between microglia and neurons via microglial CX3CR1 and its neuronal ligand is a central signaling checkpoint that shapes the immunological niche in AD. RNA sequencing studies have postulated that downregulation of microglial CX3CR1 is a neuroprotective response. By contrast, our data suggests that the loss of CX3CR1 increases accumulation of toxic, soluble Aß species which correlate with increased synaptic dysfunction, pTau pathology and neurodegeneration. Indeed, recent reports have associated CX3CR1-V249I, a mutation which impairs CX3CR1 function, with increased NFT pathology and worsened neurodegeneration in AD patients. This proposal aims to test the unique hypothesis that downregulation/loss of CX3CR1 signaling alters microglial activation and results in impaired clearance and/or increased accumulation of neurotoxic soluble Aß oligomers. Enrichment of toxic Aß in the micro-environment triggers a cascade of neurodegenerative signaling including the generation and spread of neurotoxic species of pTau. Using the single-nuclei sequencing approach we propose an unbiased genetic screen to assess how CX3CR1 alters neurodegenerative, phagocytic and neuroinflammatory signaling in early vs. late stages of AD. Results of this broad genetic analysis will be validated by a deep pathological phenotyping of the disease using 5xFAD and APPPS1 transgenic AD mice deficient in CX3CR1 signaling (Aim 1). To investigate how a toxic Aß milieu in the absence of CX3CR1 can drive neurodegeneration, we will assess the propagation and spread of pathological tau species following stereotaxic injection of toxic tau from post-mortem AD tissue into the brains of 5xFAD mice with and without CX3CR1 (Aim 2). Lastly, to understand how the human V249I variant affects neurodegenerative responses, we will use CRISPER-Cas9 technology to generate human iPSC derived microglia with CX3CR1 harboring the V429I (loss-of-function) mutation and isogenic iPS-derived AD neurons expressing M146L and L286V mutations in the PSEN1 gene. Co-culture of human-derived microglia with isogenic AD neurons will be used to assess a) how the V249I mutation shapes Aß driven neurotoxic microglial activation and b) how Aß-activated V249I+ microglia alter neuronal activity and affect neurodegenerative signalling/pathology (Aim 3). Combining the use of transgenic AD mouse models and human iPSC based in-vitro assays, this proposal will shed light on the overarching effects of CX3CR1 on Aß-driven neurodegeneration in the cascade of AD pathogenesis.


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: 2022 ( Subtotal = $136,078 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	1	12/23/2021	SUPPLEMENT FOR EXPANSION	$136,078
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	001	1	9/12/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $136,078

Issue Date FY: 2020 ( Subtotal = $3,087,997 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Aging Research	000	1	9/3/2020	NEW	$3,087,997
														Subtotal = $3,087,997

Grand Total All Awards = $3,224,075

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Deciphering the role of CX3CR1 in Modulating Mechanisms of Amyloid driven Neurodegeneration in Alzheimer's Disease (Diversity Supplement)

Award Number: RF1AG069425

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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