Protein aging hypothesis of Alzheimer disease

Abstract

Alzheimer disease (AD), the most common form of aging-related neurodegenerative disorders, is associated with formation of fibrillar deposits of amyloid β-protein (Aβ). While the direct involvement of Aβ in AD has been well documented, the relations between Aβ production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein aging-related structural transformation in soluble Aβ. We hypothesize that spontaneous chemical modification of aspartyl residues in Aβ to transient succinimide induces a non-native conformation in a fraction of soluble Aβ, rendering it amyloidogenic and neurotoxic. Conformationally altered Aβ is characterized by increased stability in solution and the presence of a non-native β-turn that determines folding of Aβ in solution and the structure of Aβ subunits incorporated into amyloid fibrils. While the soluble ‘non-native’ Aβ is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events...