Presenilin and Amyloidogenesis: A Structure-Function Relationship Study on Presenilin 2

Alzheimer’s disease (AD) is a progressive dementing neurodegenerative disorder characterized pathologically by the presence of senile plaques and neurofibrillary changes in the brains of affected individuals (1). Senile plaques are composed of amyloid β peptides (An) comprised of —40 amino acids that are proteolytically produced from ββ-amyloid precursor protein (βAPP). βAPP is initially cleaved by β-secretase to generate a 99-residue C-terminal fragment (C99) that then is cleaved by γ-secretase to generate Aβ. A subset of AD is inherited as an autosomal dominant trait (familial AD: FAD). Genetic mutations in βAPP genes that cosegregate with the clinical manifestations of FAD increase production of the amyloidogenic Aβ42 species ending at Ala42 (2); Aβ42, which normally comprises only ~10% of total secreted Aβ, aggregates much faster than the predominant Aβ40 species (3), and A342 is the initially and predominantly deposited Aβ species in AD brains (4,5). These data implicated a seminal role of Aβ42 in the pathogenesis of AD.