Abstract
The amyloid channel theory readily explains primary molecular damage induced by beta-amyloid (Aβ) but cannot interpret multiple major phenomena associated with Alzheimer's Disease such as autophagy failure and decreased metabolism. To explain them, the amyloid degradation toxicity hypothesis suggests that the cytotoxicity is initiated by the channel formation in lysosomal membranes by amyloid fragments (such as Aβ25-35 ) produced by the digestion of endocytosed Aβ. One amyloid channel is sufficient to neutralize lysosomal content and inactivate proteases; therefore, undigested amyloid accumulates, and autophagy stalls. Inadequate mitophagy results in an increased generation of reactive oxygen species and decreased energy production. Huge electrical conductance of amyloid channels prompted us to estimate the maximal size of the macromolecules which can leak from permeabilized lysosomes through amyloid channels. To estimate the channels' ability to leak molecules of various molecular weights, we modeled the channels as saline-filled cylinders in the non-conductive membranes passing spheres with a density of average globular proteins. The histograms of single channel conductance at various pH were constructed from the previously published experimental dataset. An approximation with a power function was used to extrapolate the probabilities of channels with high molecular weight cut-offs (MWCO). A variability of channel sizes suggests that channel-forming barrel-shaped aggregates can have various number of monomers. Extrapolation of the channel size distribution predicts that a significant number of channels has MWCO exceeding 10 kDa, while acidic environment disproportionally promotes their formation. This range of MWCO is sufficient for the leakage of cathepsins (20-30 kDa) implicated in the induction of necrosis and/or apoptosis. Channels with MWCO above 1000 Da can release into the cytoplasm the amyloid fragments which can form membrane channels in the plasma membrane by entering from the internal leaflet. The time needed for endocytosis and proteolytic digestion explains why cellular responses to Aβ exposure are taking significant time (at least several minutes). While dissipation of the proton gradient by small amyloid channel readily explains lysosomal failure, relatively rare events of lysosomal permeabilization to large macromolecules by amyloid channels can be an alternative mechanism of cellular death induced by the exposure to Aβ.
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More From: Alzheimer's & dementia : the journal of the Alzheimer's Association
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