Friday, May 9, 2025
5/9/2025
Roles of TREM2 and TYROBP in AD-related Network Hyperexcitability - SUMMARY Recent evidence suggests that immune and neural network dysfunctions form a vicious cycle that drives the pathogenesis of Alzheimer’s disease (AD). The triggering receptor expressed on myeloid cells 2 (TREM2) and its binding partner, the TYRO protein tyrosine kinase-binding protein (TYROBP), are both expressed by microglia, the resident immune cells of the brain. Genetic variants that impair the functions of TREM2 or TYROBP increase the risk of developing AD or other types of dementias. Several studies have demonstrated that such variants also affect the development of AD pathologies such as amyloid plaques and neurofibrillary tangles, but some of the results revealed perplexing discrepancies between effects on pathological versus functional alterations. For this and other reasons, it is important to investigate additional mechanisms, especially processes that have the potential to contribute to AD-related cognitive decline. Last year, we reported that reducing the function of TREM2 exacerbates chemically induced epilepsy in mice. Since then, we discovered similar abnormalities in mice with reduced expression of TYROBP. In addition, we found that knockin mice expressing the AD risk variant of human TREM2 R47H also have increased network hyperexcitability when challenged with an epilepsy-causing drug or when crossed onto an App knockin mouse strain that develops prominent amyloid pathology. These findings raise the possibility that microglia require TREM2 and TYROBP to suppress network hyperexcitability. The potential clinical significance of this hypothesis is highlighted by studies demonstrating nonconvulsive epileptiform activity in a substantial proportion of AD patients and a faster cognitive decline in sporadic AD patients with detectable epileptiform activity as compared to those without. While most studies of TREM2 and TYROBP have focused on genetic links to dementias or the effects of these gene products on related pathologies, our proposal will test the novel hypothesis that microglia need to express normal levels of TREM2 and TYROBP to effectively sense and suppress network hyperexcitability, which may contribute to cognitive decline in AD and related dementias. To test this overall hypothesis, we will determine whether (1) hypofunction of TYROBP exacerbates network hyperexcitability in excitotoxicity- and AD-related mouse models, (2) overexpression of TREM2 reduces chemically induced network hyperexcitability and whether TYROBP is required for this effect, and (3) how hypofunction of TREM2 or TYROBP impairs the ability of microglia to suppress aberrant neuronal activities in cell culture models. The results of the proposed experiments will shed light on the roles of these molecules and of microglia in the pathogenesis of AD. They could also provide useful guidance in the development of immune modulatory treatment for AD and related disorders.
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