Mechanistic exploration of TREM2 antibodies that can suppress alzheimer's disease related network hyperexcitability and cognitive deficits

The National Institute on Aging awarded J. David Gladstone Institutes $519,750 on September 1, 2026, under the Aging Research program (CFDA 93.866) to explore mechanistic pathways by which agonist TREM2 antibodies suppress Alzheimer's disease-related network hyperexcitability and cognitive deficits. The research investigates whether TREM2 agonism increases expression or activity of a rate-limiting enzyme involved in neuromodulator production and whether conditional ablation of this enzyme in microglia blocks the ability of agonist TREM2 antibodies to suppress network hyperexcitability in mouse models with and without amyloid plaques or TREM2 hypofunction. Work is performed in San Francisco, California with a period of performance from September 1, 2026 through August 31, 2028. This is a project grant, classified as an R21 exploratory/developmental award.

Abstract

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.