The Challenges of Modulating Neuroinflammation in Alzheimer's Disease and Multiple Sclerosis with TREM2 Agonistic Antibodies

Alzheimer's disease (AD) and multiple sclerosis (MS) are neurodegenerative diseases in which aberrant inflammatory processes are thought to contribute to progressive disability. Although MS is characterized by demyelinated lesions and AD by amyloid-β plaques and neurofibrillary tangles, both diseases involve the activation of resident macrophages known as microglia. Microglia act as central mediators of neuroinflammation through a variety of mechanisms including the release of immunomodulatory cytokines and phagocytosis of toxic debris, such as amyloid-β plaques and damaged myelin (Sen et al., 2022; Zhang et al., 2023). Acute neuroinflammation can protect the nervous system; however, dysregulation of this response can lead to chronic and damaging effects. Consequently, microglia have emerged as promising therapeutic targets for these diseases. The triggering receptor expressed by myeloid cells 2 (TREM2) is a transmembrane protein that is a key regulator of microglia (Ulland and Colonna, 2018; Zhang et al., 2023). TREM2 recognizes damage-associated lipids and amyloid-β plaques and instructs microglia to respond to pathological insults by proliferating, initiating phagocytosis, and increasing energy metabolism (Schlepckow et al., 2023; Zhang et al., 2023). Previous studies using animal models of AD and MS have shown that TREM2 is required for microglia to transition from a resting surveillance state into disease-associated microglia (DAM), which actively engage with core features of disease pathology. In AD models, TREM2 enables DAM to form protective barriers around amyloid-β plaques (Schlepckow et al., 2023). In demyelination models, used to study MS, TREM2 influences DAM recruitment to demyelination sites, clearance of myelin debris, and remyelination (Cignarella et al., 2020). Activated TREM2 is eventually cleaved, attenuating this response and releasing soluble TREM2 (sTREM2). The role of sTREM2 is unclear. It was initially considered a passive biomarker of AD pathology; however, more recent studies have shown that sTREM2 overexpression is associated with both beneficial and … Correspondence should be addressed to Juliette R. Houchois at juliette.houchois{at}medschool.ox.ac.uk.