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

Area of Science:

• Neuroscience
• Proteomics
• Alzheimer's Disease Research

Background:

• Microglial dysfunction is central to Alzheimer's disease (AD) pathology.
• Limited understanding exists regarding proteome-wide microglial changes and their functional impact during AD progression.

Purpose of the Study:

• To conduct a time-resolved proteomic analysis of microglia in mouse models of amyloid-beta (Aβ) pathology.
• To identify and characterize Microglial Aβ Response Proteins (MARPs) and their correlation with AD progression.

Main Methods:

• Proteomic characterization of microglia from APPPS1 and APP-KI mouse models of Aβ pathology.
• Time-resolved analysis across early, middle, and advanced stages of Aβ deposition.

Main Results:

• Identification of a comprehensive panel of MARPs, reflecting heterogeneous microglial alterations.
• MARP profiles emerged earlier in APPPS1 mice compared to APP-KI mice.
• Kinetic differences in proteomic profiles correlated with fibrillar Aβ, suggesting it as a trigger for microglial phenotype and functional decline.

Conclusions:

• Fibrillar Aβ, rather than dystrophic neurites, may initiate the AD-associated microglial phenotype.
• Identified microglial proteomic fingerprints serve as a resource for identifying novel molecular targets and biomarkers for AD.
• Proteomic insights can aid in monitoring AD progression and evaluating therapeutic efficacy.