Aβ Modulates Extracellular Vesicles Proteomic Profile Impacting Phosphorylation Mediators.

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaques and tau tangles.
• Extracellular vesicles (EVs) are increasingly implicated in AD pathogenesis.
• Understanding EV cargo in AD is crucial for identifying therapeutic targets.

Purpose of the Study:

• To investigate the proteomic changes in neuronal EVs under AD-mimicking conditions.
• To identify key proteins and pathways affected by Aβ treatment within EVs.
• To explore the role of EVs in the phosphorylation dynamics relevant to AD.

Main Methods:

• Isolation of EVs from N2a cells treated with Aβ.
• Mass spectrometry to analyze the EV proteome.
• Bioinformatic and network analysis to identify protein interactions and pathways.
• Assays to monitor GSK3β and protein phosphatase activity within EVs.

Main Results:

• Aβ treatment altered the proteome of neuronal EVs, affecting proteins involved in signal transduction, protein modification, and cellular dynamics.
• Enrichment or depletion of proteins related to cytoskeletal and mitochondrial function, calcium signaling, and Aβ metabolism was observed.
• Glycogen synthase kinase 3β (GSK3β) emerged as a central node in the Aβ-affected EV proteome network.
• EVs from Aβ-treated cells contained significantly different levels and activity of GSK3β and protein phosphatases compared to controls.

Conclusions:

• Neuronal EVs carry proteins crucial for phosphorylation dynamics, including GSK3β and phosphatases.
• Aβ treatment significantly modifies the proteomic cargo and activity of EVs, suggesting a role in AD progression.
• Altered EV proteomes offer potential biomarkers and therapeutic targets for Alzheimer's disease.