Abstract
Neuron. 2026 Nov 9:S0896-6273(26)00807-X. doi: 10.1016/j.neuron.2026.10.011. Online ahead of print.
ABSTRACT
Region-specific synapse loss is an early hallmark of Alzheimer's disease, yet the upstream signals that render synapses vulnerable remain unclear. In a mouse model of amyloidosis, we identify an early astrocyte state that emerges in vulnerable brain regions before widespread plaque deposition and overt gliosis. These astrocytes exhibit bulbous-looking perisynaptic processes enriched in p62 and glycogen, impaired autophagic flux and calcium signaling, and diminished astrocyte-synapse coverage. Rather than exhibiting increased synapse engulfment, bulbous astrocytes show elevated milk fat globule-epidermal growth factor 8 (MFG-E8) and are associated with increased local microglial synapse engulfment. Astrocyte-specific gain- and loss-of-function experiments demonstrate that astrocyte-derived MFG-E8 is required for microglial synapse engulfment and acts through microglial β3 integrin signaling. Astrocytic Mfge8 deletion reduces microglial engulfment and synapse loss across amyloidosis models and is associated with reduced amyloid pathology, gliosis, and cognitive impairment. Together, these findings define an astrocyte-microglia MFG-E8 signaling axis that contributes to region-specific synaptic vulnerability during early amyloid pathology.
PMID:43003089 | DOI:10.1016/j.neuron.2026.10.011
UK DRI Authors
