TY - JOUR T1 - Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid JF - bioRxiv DO - 10.1101/2021.07.31.454606 SP - 2021.07.31.454606 AU - Dmitry V. Zaretsky AU - Maria V. Zaretskaia AU - Yaroslav I. Molkov Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/08/03/2021.07.31.454606.abstract N2 - 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. Recently, we proposed the amyloid degradation toxicity hypothesis, which explains multiple major observations associated with AD – such as autophagy failure and a decreased metabolism. According to the hypothesis, the key event in the cellular toxicity of amyloid is the formation of non-selective membrane channels in lysosomal membranes by amyloid fragments that are produced by the digestion of Aβ previously absorbed by endocytosis. Electrophysiological data suggest that amyloid-formed channels have different sizes, which can be explained by the fact that barrel-shaped amyloid aggregates which create channels can consist of different number of monomers.To estimate the ability of channels to leak molecules of various molecular weights, we modeled the channels as saline-filled cylinders in non-conductive membranes that pass spheres with a density of average globular proteins. As a basis, we used the conductance distribution taken from the previously published experimental dataset, in which single channels with a conductance reaching one nanosiemens were registered. Our calculations show that channels with a giant conductance can allow for passing macromolecules such as lysosomal cathepsins implicated in the activation of apoptosis. The formation of giant channels is disproportionally promoted in an acidic environment. Also, amyloid fragments leaking from permeabilized lysosomes can reach the internal leaflet of the plasma membrane and permeabilize it.We conclude that while dissipation of the proton gradient by any – even the smallest amyloid channel – readily explains lysosomal failure, the relatively rare events of lysosomal permeabilization to large macromolecules can be an alternative mechanism of cellular death induced by exposure to Aβ.Competing Interest StatementThe authors have declared no competing interest.ADAlzheimer’s diseaseAβbeta-amyloidMWmolecular weightMWCOmolecular weight cut-off ER -