Monday, June 30, 2025 6/30/2025

Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis

Award Number: R01AG073182
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis - Abstract Alzheimer’s Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides, and intraneuronal neurofibrillary tangles, mostly composed by hyperphosphorylated tau. The impacts of AD on patients, families, caregivers and society are shattering. Regrettably, AD-modifying drugs are unavailable underscoring the scant understanding of AD pathogenesis. ~5% of AD cases have early onset (<65 yo) and are due to Familial autosomal dominant mutations in APP, PSEN1 and PSEN2 (FAD); ~95% of cases are sporadic with late onset (>65 yo, SAD). Yet, commonly used animal organisms model FAD. This may be an issue if FAD and SAD present significant pathogenic differences. If so, therapeutics effective in FAD animals may have limited efficacy in SAD patients. Thus, models that reproduce the pathogenesis of SAD are needed to identify therapeutic targets and test SAD-modifying therapeutics. Variants of the microglia gene TREM2 increase the risk of SAD by 3 fold. To gain insights into the pathogenic mechanisms of SAD, we generated rats carrying the p.R47H pathogenic variant in the rat Trem2 gene (Trem2R47H). Rat and human APP differ by 3 amino acids in the Aβ region. These differences may be crucial in this model organism because: 1) human Aβ possesses higher propensity to form toxic species as compared to rodent Aβ; 2) the pathogenic role of the p.R47H TREM2 variant may be linked to deficits in microglia-mediated human Aβ clearance. To overcome this issue, we humanized the rat Aβ sequence (Apph allele); thus, our rat models produce human Aβ from the endogenous rat App gene. We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Ab and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Ab have a central pathogenic role. We propose to dissect pathogenic mechanisms triggered by the p.R47H pathogenic variant using these KI rat models. We will also study the impact of Trem2R47H on the pathological processes triggered by the Apps and Psen1LF FAD mutations. We will analyze microglia function, cell-to-cell transcriptomic changes in the brain, APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. Dissecting pathogenic pathways set off by the Trem2R47H variant may pave the way to therapeutic approaches that can prevent/delay sporadic AD.


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 = $766,821 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	000	5	3/25/2025	NON-COMPETING CONTINUATION	$704,224
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	5	6/18/2025	NON-COMPETING CONTINUATION	$62,597
														Subtotal = $766,821

Issue Date FY: 2024 ( Subtotal = $782,471 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	002	4	4/16/2024	NON-COMPETING CONTINUATION	$782,471
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	3	12/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$372,024
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	2	12/1/2023	NON-COMPETING CONTINUATION	-$372,024
														Subtotal = $782,471

Issue Date FY: 2023 ( Subtotal = $782,471 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	003	3	8/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$782,471
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	001	3	4/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$782,471
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Aging Research	002	3	8/9/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$782,471
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	2	4/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $782,471

Issue Date FY: 2022 ( Subtotal = $782,471 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	2	4/20/2022	NON-COMPETING CONTINUATION	$782,471
														Subtotal = $782,471

Issue Date FY: 2021 ( Subtotal = $782,471 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Aging Research	000	1	7/30/2021	NEW	$782,471
														Subtotal = $782,471

Grand Total All Awards = $3,896,705

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Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis

Award Number: R01AG073182

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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