Mitochondria: the common upstream driver of amyloid-β and tau pathology in Alzheimer's disease.
Mitochondrial dysfunction has been widely implicated in the etiology of Alzheimer's 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 sirtuin-mediated 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.
Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-Coimbra, Portugal.
D F F
DF
Silva
A R
AR
Esteves
C R
CR
Oliveira
S M
SM
Cardoso
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins