title: Amyloid-β-induced mitochondrial dysfunction impairs the autophagic lysosomal pathway in a tubulin dependent pathway.
abstract: Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-β (Aβ) peptides are known to interact with several proteins inside the mitochondria, leading to mitochondrial dysfunction. Recent studies have provided substantial evidence that mitochondria serve as direct targets for Aβ-mediated neuronal toxicity. The observations that Aβ progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial Aβ in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by Aβ-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that Aβ peptides induced an increase in NAD+levels and a decrease in ATP levels, which was related with decreases in acetylated tubulin levels and tau hyperphosphorylation. As a result of microtubule disruption, alterations in macroautophagy, like a decrease in autophagossome degradation and altered cellular distribution of LC3B, were found. Taxol, a microtubule stabilizer drug, was able to restore microtubule network and to prevent cell death induced by Aβ peptides. Our data shows for the first time that mitochondrial and cytosolic Aβ oligomers were significantly reduced upon microtubule dynamics re-establishment. These observations point out that an intervention at a microtubule level may be effective as a disease modifying therapy.
authors.affiliation: Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: Diana F F
authors.initials: DF
authors.lastname: Silva
authors.forename: A Raquel
authors.initials: AR
authors.lastname: Esteves
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Arduino
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Oliveira
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004396:Coloring Agents; D003576:Electron Transport Complex IV / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D051336:Mitochondrial Membranes / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin / Q000502:physiology*
chemical_list: D000227:Adenine Nucleotides; D016229:Amyloid beta-Peptides; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; C078592:amyloid beta-protein (1-40); D009243:NAD; D003576:Electron Transport Complex IV; D020169:Caspases; C022616:thiazolyl blue; D017239:Paclitaxel