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PHF6 reduced the lipid fluidity of cardiolipin/DOPC vesicles (that mimic the IMM) but not DOPC (which mimics the outer mitochondrial membrane), and this effect was inhibited by Aβ42DM. This inhibition may be explained by the conformational changes in PHF6 induced by Aβ42DM in solution and in membrane mimetics. On this basis, the paper presents a mechanistic explanation for the inhibitory activity of Aβ42DM against Aβ42- and tau-induced membrane permeability and cell toxicity and provides confirmatory evidence for its protective functio