Investigating the Effects of TREM2 Modulation with In-Vitro Models & Profiling the Proteome of Alzheimer’s Disease (and other Neurological Diseases) Cerebrospinal Fluid

Alzheimer's Disease (AD) is a progressive neurodegenerative disease, and is most often characterized by two main pathologies, extracellular β-amyloid plaques (Aβ) and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The development and progression of AD is associated with chronic inflammation in the central nervous system (CNS), which is largely influenced by microglia, the resident immune cells of the CNS. Triggering receptor on myeloid cells 2 (TREM2), is a key receptor protein expressed by microglia and is involved in many microglial functions. TREM2 is also one of the most strongly associated genes with AD risk, and as such, has garnished much attention from the field as a therapeutic target. We sought to understand how unique methods of TREM2 modulation can differentially impact microglial functions, utilizing therapeutically relevant anti-TREM2 antibodies. Additionally, we profiled cerebrospinal fluid (CSF) from AD (and other neurological disease) patients using an innovative, ultra-sensitive technology, in an attempt to identify differentially expressed proteins in AD CSF that are related to microglial function. Our results demonstrate that differences in TREM2 activation in-vitro have distinct effects on microglial function, specifically on chemokine release and cell viability. We also identify proteins associated with microglial function that are differentially expressed in AD CSF, warranting further investigation as possible biomarkers of glial and inflammatory biology.