Amyloid-β-induced mitochondrial dysfunction impairs the autophagic lysosomal pathway in a tubulin dependent pathway.

J Alzheimers Dis

Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.

Published: January 2012

AI Article Synopsis

  • Mitochondrial dysfunction is linked to Alzheimer's disease (AD), with amyloid-β (Aβ) peptides disrupting mitochondrial function and contributing to neuronal toxicity.
  • Recent research shows that Aβ accumulation in mitochondrial structures may play a significant role in the disease's development, impacting cellular metabolic pathways and leading to altered levels of NAD+ and ATP.
  • Restoration of microtubule dynamics using the drug Taxol showed promising results in reducing Aβ levels and preventing cell death, suggesting that targeting microtubule stability could be a potential therapeutic approach in treating AD.

Article 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.

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Source
http://dx.doi.org/10.3233/JAD-2011-110423DOI Listing

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