A novel monomeric amyloid β-activated signaling pathway regulates brain development via inhibition of microglia

Abstract

Amyloid {beta} (A{beta}) forms aggregates in the Alzheimers disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether A{beta} also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of A{beta} in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during development in vivo. We find that activation of this pathway depends on the function of amyloid precursor (APP) and the heterotrimeric G protein regulator Ric8a in microglia and inhibits microglial immune activation at transcriptional and post-transcriptional levels. Genetic disruption of this pathway during neocortical development results in microglial dysregulation and excessive matrix proteinase activation, leading to basement membrane degradation, neuronal ectopia, and laminar disruption. These results uncover a previously unknown function of A{beta} as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of A{beta} and neuroinflammation in the pathology of Alzheimers disease, they also highlight a potentially overlooked role of A{beta} monomer depletion in the development of the disease.