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

Male Proteome QH301-705.5 Science microglia Mice, Transgenic neuroinflammation Amyloid beta-Protein Precursor Mice proteomic signatures Alzheimer Disease Animals Gene Knock-In Techniques Biology (General) Amyloid beta-Peptides Q R phagocytosis Alzheimer's disease 3. Good health Disease Models, Animal Medicine Female Microglia ddc:600 Neuroscience
DOI: 10.7554/elife.54083 Publication Date: 2020-06-08T11:00:17Z
ABSTRACT
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.
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