Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques

In Alzheimer's disease (AD), beta-amyloid (A beta) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque micro-regions with low A beta 42 affinity. Areas uncovered by microglia are less compact but have high A beta 42 affinity, leading to the formation of protofibrillar A beta 42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar A beta 42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-A beta immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar A beta hotspots may constitute novel therapeutic and clinical imaging targets for AD.