Innate Immunity in Alzheimer’s Disease: A Complex Affair

Alzheimer’s disease (AD) is characterized by three major histopathological hallmarks: β-amyloid deposits, neurofibrillary tangles and gliosis. While neglected for decades, the neuroinflammatory processes coordinated by microglia are now accepted as etiologic events in AD evolution. Microglial cells are found in close vicinity to amyloid plaques and display various activation phenotypes determined by the expression of a wide range of cytokines, chemokines, and innate immune surface receptors. During the development of AD pathology, microglia fail to restrict amyloid plaques and may contribute to neurotoxicity and cognitive deficit. Nevertheless, under specific activation states, microglia can participate in cerebral amyloid clearance. This review focuses on the complex relationship between microglia and Aβ pathology, and highlights both deleterious and beneficial roles of microglial activation states in the context of AD. A deeper understanding of microglial biology will hopefully pave the way for next-generation AD therapeutic approaches aimed at harnessing these enigmatic innate immune cells of the central nervous system.