Mini-review: Amyloid degradation toxicity hypothesis of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people. Neuronal death in AD is initiated by oligomeric amyloid-β (Aβ) peptides. The amyloid channel hypothesis readily explains the primary molecular damage but does not address major observations associated with AD such as autophagy failure and decreased metabolism. The amyloid degradation toxicity hypothesis provides the interpretation as a sequence of molecular events. Aβ enters a cell by endocytosis, and the endocytic vesicle is merged with a lysosome. Lysosomal peptidases degrade the peptide. Fragments form membrane channels in lysosomal membranes that have a significant negative charge due to the presence of acidic phospholipids. Amyloid channels can transfer various ions (including protons) and even relatively large compounds, which explains lysosomal permeabilization. The neutralization of lysosomal content inactivates degradation enzymes, results in an accumulation of undigested amyloid, and stalls autophagy. Inadequate quality control of mitochondria is associated with an increased production of reactive oxygen species and decreased energy production. Also, the passage of lysosomal proteases through rare extremely large channels results in cell death. Proposed hypothesis identifies biochemical pathways involved in the initiation and progression of cellular damage induced by beta-amyloid and provides new potential pharmacological targets to treat Alzheimer’s disease.