Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models

作者：Laura Sebastián Monasor, Stephan A. Müller, Alessio Colombo, Gaye Tanrioever, Jasmin König, Stefan Roth, Arthur Liesz, Anna Berghofer, Anke Piechotta, Matthias Prestel, Takashi Saito, Takaomi C. Saido, Jochen Herms, Michael Willem, Christian Haass, Stefan F. Lichtenthaler, Sabina Tahirović · 发表于：eLife · 年份：2020 · DOI：10.7554/elife.54083 · 被引用次数：143 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Neurological Disease Mechanisms and Treatments

Microglial dysfunction is a key pathological feature of Alzheimer's disease (AD), but little is known about proteome-wide changes in microglia during the course of AD and their functional consequences. Here, we performed an in-depth and time-resolved proteomic characterization of microglia in two mouse models of amyloid β (Aβ) pathology, the overexpression APPPS1 and the knock-in APP-NL-G-F (APP-KI) model. We identified a large panel of Microglial Aβ Response Proteins (MARPs) that reflect heterogeneity of microglial alterations during early, middle and advanced stages of Aβ deposition and occur earlier in the APPPS1 mice. Strikingly, the kinetic differences in proteomic profiles correlated with the presence of fibrillar Aβ, rather than dystrophic neurites, suggesting that fibrillar Aβ may trigger the AD-associated microglial phenotype and the observed functional decline. The identified microglial proteomic fingerprints of AD provide a valuable resource for functional studies of novel molecular targets and potential biomarkers for monitoring AD progression or therapeutic efficacy.