Mining Alzheimer's Interactomes, Macromolecular Complexes and Pathways for Drug Discovery.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing dementia, with no cure.
• Understanding AD's molecular basis is crucial for developing effective treatments.
• Mapping genetic variants to molecular interactions offers insights into disease pathways.

Purpose of the Study:

• To identify how Alzheimer's disease-associated mutations alter protein interactions and regulatory networks.
• To uncover variant-specific disrupted pathways in brain tissues.
• To explore therapeutic targets by analyzing protein interactors of amyloid precursor protein (APP).

Main Methods:

• Differential interactome analysis on a curated AD dataset.
• Mapping variant-specific protein interactions in brain-relevant tissues.
• Reactome enrichment analysis and integration of microRNA (miRNA)-mediated regulation.

Main Results:

• Identified alterations in both transient and stable protein interactions due to AD mutations.
• Discovered variant-specific disruptions in macromolecular assemblies and perturbed pathways.
• Revealed miRNA-mediated posttranscriptional control over key AD genes and identified APP interactor-based therapeutic targets.

Conclusions:

• A multilayered strategy provides a framework for understanding AD molecular networks.
• This approach facilitates the identification of precision therapeutic strategies for Alzheimer's disease.
• Mapping genetic variants to interactomes enhances our understanding of AD pathogenesis.