Membrane channel hypothesis of lysosomal permeabilization by beta-amyloid

• Published in: Neuroscience letters 2022-01, Vol.770, p.136338-136338, Article 136338
• Main Authors: Zaretsky, Dmitry V., Zaretskaia, Maria V., Molkov, Yaroslav I.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Apoptosis; Beta-amyloid; Cell death; Cell Membrane - metabolism; Cell Membrane Permeability; Humans; Lipid Bilayers - metabolism; Lysosomal permeabilization; Lysosome; Lysosomes - metabolism; Membrane channel; Membrane Potentials
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2021.136338

[Display omitted] •Exposure of cells to beta-amyloid results in lysosomal permeabilization.•Degradation products of beta-amyloid can form non-selective membrane channels.•Based on existing electrophysiological data we predict that amyloid channels can be large enough to pass macromolecules.•Different mechanisms of cell death are possible after beta-amyloid exposure depending on lysosomal membrane channel size. 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 including 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 channel creating barrel-shaped amyloid aggregates 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 electrical conductance of up to one nanosiemens were registered. Our calculations show that channels with such a giant conductance can allow for passing macromolecules such as large 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 smallest) amyloid channels readily explains lysosomal failure, the relatively rare events of lysosomal permeabilization to large macromolecules can be an additional mechanism of cellular death induced by exposure to Aβ.