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Investigating neutrophilic inflammation as an APOE genotype-specific mediator of cognitive decline and reduced synaptic plasticity in aging

Award Number: R56AG079224
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Investigating neutrophilic inflammation as an APOE genotype-specific mediator of cognitive decline and reduced synaptic plasticity in aging - PROJECT SUMMARY The presence of the epsilon4 allele of APOE (APOE4) is the greatest genetic risk factor for late onset Alzheimer’s disease, increasing the risk approximately 12-fold when homozygous for APOE4 compared to the most common APOE3/APOE3 genotype. However, the mechanisms by which different APOE alleles mediate Alzheimer’s risk is unclear. The overall goals for this study are to 1) Investigate neutrophil activation and lifespan as therapeutic targets to reduce Alzheimer’s disease risk or progression in the context of different APOE genotypes and 2) Identify microbial interactions that represent promising targets to reduce neutrophilic inflammation in the context of different APOE genotypes. A multitude of data demonstrate that individuals with different APOE genotypes vary in their responses to inflammatory stimuli, and ApoE- modulated neuroinflammation is emerging as a potential new mediator of ApoE-specific cognitive decline. We propose that the gastrointestinal and peripheral immune systems represent a likely bridge between infection or microbial dysbiosis and neuroinflammation, and that neutrophils, as the most abundant leukocyte with great potential for inflammatory damage, mediate altered responses in individuals with different APOE alleles to drive cognitive decline. Our hypothesis is that APOE4 increases neutrophil activation and lifespan in the GI, periphery, and brain, thus contributing to cognitive decline and reduced synaptic plasticity in individuals with the APOE4 allele. This hypothesis is based on compelling evidence from published work and our preliminary data. Studies have demonstrated that neutrophils infiltrate the brain vasculature and parenchyma during AD and neutrophil activation in the periphery corresponds with disease progression in AD. Our preliminary data suggests that ApoE alters neutrophil activation to inflammatory stimuli in an isotype-specific manner, as has been observed previously in glial cells. We will address our hypothesis and achieve our study goals by pursuing the following three aims: 1) Examine neutrophil activation, lifespan, and function in the GI tract, periphery, and brain throughout the lifespan in mice expressing human APOE2, APOE3, and APOE4 under the endogenous promotor (APOE-TR); 2) Investigate roles of the microbiome and bacteria-neutrophil interactions in APOE-specific neutrophil alterations, and 3) Determine if neutrophils mediate neuroinflammation and cognitive decline in an APOE- specific manner in response to low level inflammatory stimuli via neutrophil depletion studies. This project is significant because no studies have investigated APOE-specific neutrophil responses despite a proposed role for neutrophils in Alzheimer’s disease. This project is translationally innovative and actionable because the information gained will inform the testing of neutrophil-targeted or microbial-targeted therapeutic approaches in Alzheimer’s disease mouse models and humans and determine if they should be tailored based on APOE genotype.


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: 2024 ( Subtotal = $0 )
2024	2022	THE MCLAUGHLIN RESEARCH INSTITUTE FOR BIOMEDICAL SCIENCES, INC.	1520 23RD ST S	GREAT FALLS	MT	59405	CASCADE	USA	Aging Research	000	1	5/1/2024	NEW	$0
2024	2022	THE MCLAUGHLIN RESEARCH INSTITUTE FOR BIOMEDICAL SCIENCES, INC.	1520 23RD ST S	GREAT FALLS	MT	59405	CASCADE	USA	Aging Research	001	1	9/11/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $450,000 )
2022	2022	MCLAUGHLIN RESEARCH INSTITUTE FOR BIOMEDICAL SCIENCES, INC., THE	1520 23RD ST S	GREAT FALLS	MT	59405	CASCADE	USA	Aging Research	000	1	9/15/2022	NEW	$450,000
														Subtotal = $450,000

Grand Total All Awards = $450,000

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Investigating neutrophilic inflammation as an APOE genotype-specific mediator of cognitive decline and reduced synaptic plasticity in aging

Award Number: R56AG079224

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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