Abstract
In Alzheimer’s disease (AD), β-amyloid (Aβ) 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 microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In aging, microglia coverage is reduced, leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD.
Highlights
In Alzheimer’s disease (AD), b-amyloid (Ab) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown
In our analysis of confocal image stacks of brain slices with labelled microglia and fibrillar amyloid plaques, we observed that larger plaques tended to have less microglia coverage than smaller ones, but overall there was a great heterogeneity in the degree of microglia coverage (Fig. 1a,b)
We found that over intervals of minutes to days, the microglial processes wrapping plaques were highly stable in contrast to the motile processes in the same cells that were not contacting plaques (Fig. 1c–g and Supplementary Movie 1)
Summary
In Alzheimer’s disease (AD), b-amyloid (Ab) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. It remains unknown whether the aspects of microglia function play beneficial or detrimental roles that could be targeted for therapeutic purposes To address this gap in knowledge, we developed in vivo methods using two-photon and high-resolution confocal microscopy for examining the role of microglia in the dynamic equilibrium between soluble interstitial Ab and fibrillar amyloid deposits, amyloid plaque expansion and the resulting toxicity to adjacent neurons. Our data reveal a striking pattern of anti-colocalization between microglia processes, protofibrillar Ab42 and dystrophic axons We demonstrate that this pattern is due to microglia acting as a barrier that restricts the radial expansion of plaques by controlling their affinity for soluble Ab, a function that we show is critical for limiting the formation of neurotoxic hotspots of protofibrillar Ab42 around plaques. We show that certain natural and synthetic small molecules have the ability to selectively target these neurotoxic protofibrillar Ab42 hotspots, raising the possibility that analogous compounds could be used therapeutically or in clinical imaging applications
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