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

• Published in: Nature communications 2015-01, Vol.6 (1), p.6176-6176, Article 6176
• Main Authors: Condello, Carlo, Yuan, Peng, Schain, Aaron, Grutzendler, Jaime
• Format: Article
• Language: English
• Subjects: 14/19; 14/34; 14/69; 631/378/1689/1283; 631/378/2596/1953; Aging; Amyloid - metabolism; Amyloid beta-Peptides - metabolism; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Brain - drug effects; Brain - pathology; Coloring Agents - metabolism; CX3C Chemokine Receptor 1; Diffusion; Female; Gene Deletion; Humanities and Social Sciences; Humans; Immunization; Male; Mice; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; multidisciplinary; Neurites - drug effects; Neurites - metabolism; Neuroprotective Agents - pharmacology; Neurotoxins - metabolism; Peptide Fragments - metabolism; Plaque, Amyloid - metabolism; Receptors, Chemokine - metabolism; Science; Science (multidisciplinary); Solubility; Staining and Labeling
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7176

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 the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, 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. In Alzheimer’s disease (AD), β-amyloid plaques are tightly enveloped by microglia but the significance of this phenomenon is unknown. Here the authors used confocal and in vivo two-photon imaging in AD mouse models and revealed that microglia constitute a barrier that seems to prevent the formation of neurotoxic hotspots of protofibrillar β-amyloid.