Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) aggregation, forming oligomers and plaques.
• Aggregation-prone regions (APRs) in Aβ are key for protein interactions during aggregation.
• Understanding proteins interacting with soluble Aβ in the human brain is crucial for AD pathogenesis.

Purpose of the Study:

• To systematically identify proteins interacting with soluble Aβ in the human cortex across the AD continuum.
• To investigate early changes in the Aβ interactome in asymptomatic and symptomatic AD.
• To correlate protein interactions with neuropathological staging in AD.

Main Methods:

• Affinity purification-mass spectrometry using Aβ-specific antibodies (4G8, 6E10) and a non-specific control.
• Differential expression analysis to identify the 'Aβ interactome'.
• Co-expression network analysis and diagnostic group comparisons to assess correlations with AD pathology.

Main Results:

• Identified 129 proteins in the Aβ interactome, including APOE, GFAP, vimentin.
• Discovered a protein module negatively correlated with Aβ severity.
• Found reduced levels of proteins involved in cytoskeletal modeling, endocytosis, chaperone function, and Rho GTPase activity in early AD stages.

Conclusions:

• Interactions of Aβ with proteins in septins, clathrin-mediated endocytosis, and chaperone functions are diminished in AD, even in asymptomatic individuals.
• Impaired physiological protein-binding of soluble Aβ may be an early pathogenic event in AD development.