APP/Aβ structural diversity and Alzheimer's disease pathogenesis

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Abstract

The amyloid cascade hypothesis of Alzheimer's disease (AD) proposes amyloid- β (Aβ) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Aβ 1–40 and 1–42 peptides. However, alternative APP proteolytic processing produces a complex roster of Aβ species. In addition, Aβ peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Aβ species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration. We surveyed the literature to catalog Aβ PTM including species with isoAsp at positions 7 and 23 which may phenocopy the Tottori and Iowa Aβ mutations that result in early onset AD. We speculate that accumulation of these alterations induce changes in secondary and tertiary structure of Aβ that favor increased toxicity, and seeding and propagation in sporadic AD. Additionally, amyloid-β peptides with a pyroglutamate modification at position 3 and oxidation of Met35 make up a substantial portion of sporadic AD amyloid deposits. The intrinsic physical properties of these species, including resistance to degradation, an enhanced aggregation rate, increased neurotoxicity, and association with behavioral deficits, suggest their emergence is linked to dementia. The generation of specific 3D-molecular conformations of Aβ impart unique biophysical properties and a capacity to seed the prion-like global transmission of amyloid through the brain. The accumulation of rogue Aβ ultimately contributes to the destruction of vascular walls, neurons and glial cells culminating in dementia. A systematic examination of Aβ PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions.

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