Mitochondrial dysfunction has been widely implicated in the etiology of Alzheimers disease (AD). Evidence shows a mitochondrial-mediated impairment of autophagy that potentiates amyloid-β (Aβ) deposition. Accordingly, recent data obtained from AD models, in which mitochondrial alterations are a prominent feature, demonstrated abnormalities in microtubule network, involving tubulin and tau post-translational modifications. In this review we will discuss mitochondrial- regulated processes where mitochondrial malfunction is likely to start a sequence of events leading to sirtuin- 2 activation, microtubule network breakdown, and impairment of the autophagic pathway. Because sirtuin-2 activity depends on cellular NAD+ availability, mitochondrial regulation of NAD+ levels may contribute to an increase in sirtuinmediated tubulin deacetylation. A vicious cycle become installed which potentiates tau hyperphosphorylation, together with Aβ overproduction and deposition. Overall, targeting microtubule network constitutes a promising strategy for pharmacological therapy in AD.
Keywords: Alzheimer's disease, amyloid-β, autophagy, microtubule network, mitochondria, tau, calcium homeostasis, oxidative phosphorylation, AD development, oxidative stress markers, neurodegeneration, mitochondrial integrity, resonance spectroscopy
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