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

• DOI: 10.1523/jneurosci.1869-24.2024
• Publication Date: 2024-12-16T13:44:47Z
• Authors: Juliette R. Houchois; Jonathan E. Attwood
• Keywords: TREM2; Remyelination

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