Amyloid β (Aβ) forms aggregates in the Alzheimer’s disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ 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 Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during mouse development in vivo. We find that activation of this pathway depends on the function of amyloid precursor 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 Aβ as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of Aβ and neuroinflammation in the pathology of Alzheimer’s disease, they also highlight a potentially overlooked role of Aβ monomer depletion in the development of the disease.

Language is acquired and processed in complex and dynamic naturalistic contexts, involving the simultaneous processing of connected speech, faces, bodies, objects, etc. How words and their associated concepts are encoded in the brain during real-world processing is still unknown. Here, the representational structure of concrete and abstract concepts was investigated during movie watching to address the extent to which brain responses dynamically change depending on visual context. First, across contexts, concrete and abstract concepts are shown to encode different experience-based information in separable sets of brain regions. However, these differences are reduced when multimodal context is considered. Specifically, the response profile of abstract words becomes more concrete-like when these are processed in visual scenes highly related to their meaning. Conversely, when the visual context is unrelated to a given concrete word, the activation pattern resembles more that of abstract conceptual processing. These results suggest that while concepts generally encode habitual experiences, the underlying neurobiological organisation is not fixed but depends dynamically on available contextual information.