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Mechanistic Exploration of TREM2 Antibodies that Can Suppress Alzheimer's Disease Related Network Hyperexcitability and Cognitive Deficits

Award Number: R21AG101017
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Mechanistic Exploration of TREM2 Antibodies that Can Suppress Alzheimer's Disease Related Network Hyperexcitability and Cognitive Deficits - SUMMARY Alzheimer’s disease (AD), the most common neurodegenerative disorder, is associated with hyperexcitability of neural networks and immune cell dysfunction. Our previous studies showed that AD-related network and immune dysfunctions may engage in a vicious circle that contributes to synaptic alterations and cognitive decline. Our most recent findings suggest that this circle can be disrupted by treatment with agonist antibodies targeting the triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor that, in the brain, is expressed primarily by microglia. Here we propose to explore the novel concept that agonist TREM2 antibodies reduce AD-related network hyperexcitability and cognitive deficits by increasing the production of a neuromodulator that can inhibit neuronal activities. To our knowledge, TREM2 has not yet been linked to the pathways that regulate this neuromodulator, which makes this a daring concept to explore. Yet, the identification of such a link could shed new light on the pathogenesis of AD, the neurobiology of TREM2, and the mechanism of action of novel therapeutics that are in preclinical development or early stages of clinical assessment, highlighting the potential impact of the proposed study. In Aim 1, we will explore whether agonist TREM2 antibodies increase the expression or activity of a rate-limiting enzyme involved in the production of the neuromodulator and begin to dissect the signaling pathways involved. In Aim 2, we will explore whether conditional ablation of this enzyme in microglia blocks the ability of agonist TREM2 antibodies to suppress network hyperexcitability in mouse models that do or do not have amyloid plaques or TREM2 hypofunction. These experiments have the potential to (i) elucidate the biochemical processes by which TREM2 agonism allows microglia to counteract network hyperexcitability, (ii) identify an entirely novel link between TREM2 and the regulation of an enzyme involved in the production of a key neuromodulator, and (iii) begin to unravel the molecular mechanisms underlying this link, which could identify novel entry points for therapeutic interventions. Augmenting the availability of potent neuromodulators through treatments with agonist antibodies or small molecules that enhance TREM2-dependent signaling pathways could provide an effective strategy to curtail network hyperexcitability and related cognitive impairments in AD and other conditions associated with excitation/inhibition imbalance of neural networks such as epilepsy and neuropsychiatric disorders, further broadening the therapeutic implications of this project.


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 = $519,750 )
2026	2026	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Aging Research	000	1	9/1/2026	NEW	$519,750
														Subtotal = $519,750

Grand Total All Awards = $519,750

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Mechanistic Exploration of TREM2 Antibodies that Can Suppress Alzheimer's Disease Related Network Hyperexcitability and Cognitive Deficits

Award Number: R21AG101017

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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