Alzheimer's Disease: A Molecular Model and Implied Path to Improved Therapy

Area of Science:

• Neurodegenerative diseases
• Protein misfolding
• Innate immunity

Background:

• Amyloid-associated diseases like Alzheimer's (AD) involve β-sheet amyloid accumulation.
• Current disease models and therapies for amyloidosis are lacking.
• Amyloid-forming proteins may possess innate immunity functions via α-sheet conformations.

Approach:

• Reviewed existing data and presented a novel hypothesis on amyloid protein function.
• Investigated the effect of methylene blue (MB) on phage T4 capsid structure using electron microscopy and native gel electrophoresis.
• Proposed a corollary hypothesis linking MB's anti-AD effects to α-sheet binding and T4 capsid subunit transitions.

Key Points:

• Amyloid proteins may function in innate immunity by forming α-sheets that inactivate microbes.
• In disease, over-accumulated α-sheet proteins become neurotoxic.
• Methylene blue (MB) at 54°C induced significant structural changes in phage T4 capsids.

Conclusions:

• MB's anti-AD activity may stem from binding to amyloid α-sheets.
• MB might induce transitions to the α-sheet conformation in viral capsid subunits.
• Native gel electrophoresis of drug-incubated T4 phage can serve as a model to screen for improved anti-AD compounds.