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

ELife
Laura Sebastian MonasorSabina Tahirovic

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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Datasets Mentioned

BETA
AB947
PXD016075

Methods Mentioned

BETA
fluorescence activated cell sorting
glycosylation
transgenic
Fluorescence
FACS
mechanical dissociation
protein assay
confocal microscopy
FCS
flow cytometry

Software Mentioned

Maxquant
DIA
Biognosys
ImageJ
Spectronaut
DAVID
Treestar
FlowJo

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