Microglia constitute a barrier that prevents neurotoxic protofibrillar Ab42 hotspots around plaques

In Alzheimer’s disease (AD), b-amyloid (Ab) 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 highresolution 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 microregions with low Ab42 affinity. Areas uncovered by microglia are less compact but have high Ab42 affinity, leading to the formation of protofibrillar Ab42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar Ab42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Ab immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Ab hotspots may constitute novel therapeutic and clinical imaging targets for AD.