Amyloid-β-Induced Mitochondrial Dysfunction Impairs the Autophagic Lysosomal Pathway in a Tubulin Dependent Pathway

Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain and peripheral tissues. Amyloid-beta (A beta) 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 A beta-mediated neuronal toxicity. The observations that A beta progressively accumulates in cortical mitochondria from AD patients and transgenic AD type mouse models suggest the role of mitochondrial A beta in the pathogenesis or development of AD. Herein, we studied the downstream signaling pathways induced by A beta-mediated mitochondrial metabolism alterations and its consequences on cellular fate. We found that A beta 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 the microtubule network and to prevent cell death induced by A beta peptides. Our data shows for the first time that mitochondrial and cytosolic A beta 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.