Monomeric amyloid-β inhibits microglial inflammatory activity in the brain via an APP/heterotrimeric G protein-mediated pathway

Abstract

SUMMARYMicroglia, the resident immune cell of the brain, play critical roles in brain development, function, and disease. However, how microglial activity is regulated in this process remains to be elucidated. Here we report an amyloid precursor protein (APP) and heterotrimeric G protein-mediated pathway that negatively regulates microglial inflammatory activation during cerebral cortex development. Disruption of this pathway results in dysregulated microglial activity, excessive extracellular matrix proteinase production, cortical basement membrane breach, and laminar assembly disruption. We further show that this pathway is activated by amyloid β (Aβ), the cleavage product of APP that accumulates in large quantities as plaques in the Alzheimer’s disease brain. Specifically, we find Aβ monomers potently suppress inflammatory cytokine transcription and secretion by brain microglia, in an APP and heterotrimeric G protein-dependent manner. These results discover a previously unknown activity of Aβ as a negative regulator of brain microglia as well as a new pathway that mediates the signal transduction. They shed new light on the cell-cell communication mechanisms that regulate brain immune homeostasis and may facilitate further insight into Alzheimer’s disease pathogenesis.