title: Amyloid-β and the failure to form mitochondrial cristae: a biomimetic study involving artificial membranes.
abstract: Alzheimer's disease (AD) is a degenerative disease of the central nervous system which causes irreversible damage to neuron structure and function. The main hypothesis concerning the cause of AD is excessive accumulation of amyloid-β peptides (Aβ). There has recently been a surge in studies on neuronal morphological and functional pathologies related to Aβ-induced mitochondrial dysfunctions and morphological alternations. What is the relation between the accumulation of Aβ in mitochondria, decreased production of ATP, and the large number of mitochondria with broken or scarce cristae observed in AD patients' neurons? The problem is complex, as it is now widely recognized that mitochondria function determines mitochondrial inner membrane (IM) morphology and, conversely, that IM morphology can influence mitochondrial functions. In our previous work, we designed an artificial mitochondrial IM, a minimal model system (giant unilamellar vesicle) mimicking the IM. We showed experimentally that modulation of the local pH gradient at the membrane level of cardiolipin-containing vesicles induces dynamic membrane invaginations similar to the mitochondrial cristae. In the present work we show, using our artificial IM, that Aβ renders the membrane unable to support the formation of cristae-like structures when local pH gradient occurs, leading to the failure of this cristae-like morphology. Fluorescent probe studies suggest that the dramatic change of membrane mechanical properties is due to Aβ-induced lipid bilayer dehydration, increased ordering of lipids, loss of membrane fluidity, and possibly to Aβ-induced changes in dynamic friction between the two leaflets of the lipid membrane.
authors: UPMC Univ. Paris 6, UMR_S 938, CDR St Antoine, F-75012, Paris, France.
authors: Nada
authors: N
authors: Khalifat
authors: Nicolas
authors: N
authors: Puff
authors: Mariam
authors: M
authors: Dliaa
authors: Miglena I
authors: MI
authors: Angelova
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D040761:Biomimetic Materials / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D008560:Membrane Fluidity / Q000502:physiology; D008567:Membranes, Artificial; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D008567:Membranes, Artificial; D010446:Peptide Fragments