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

• Main Authors: Laura Sebastian Monasor, Stephan A Müller, Alessio Vittorio 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 Tahirovic
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-06-01
• Series: eLife
• Subjects: Alzheimer's disease; microglia; proteomic signatures; neuroinflammation; phagocytosis
• Online Access: https://elifesciences.org/articles/54083

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.