Diana F Silva
Center for Neuroscience and Cell Biology, Portugal
Diana F Silvia is currently pursuing her PhD at Center for Neuroscience and Cell Biology at the University of Coimbra, Portugal. Since 2009 she has been interested on understanding the pathophysiologic mechanisms of Alzheimer´s disease from a mitochondrial point of view. She has been able to describe that mitochondrial dysfunction starts a sequence of events leading to cell demise in AD models, in a team work between the University of Coimbra and University ok Kansas Medical Center, USA. These observations can be accessed on more than 10 papers published in peer reviwed journals.
Mitochondrial abnormalities have been widely described in several tissues in sporadic Alzheimer´s disease (sAD) patients and mild cognitive impairment (MCI) individuals. In 2004 Mitochondrial Cascade Hypothesis for sAD was proposed and asserts that inheritance determines baseline mitochondrial function and durability. When a particular mitochondrial functional threshold is reached within AD relevant neurons, the neurodegenerative process emerges. In this study, cells bearing mitochondrial DNA from MCI and AD subjects and age-matched controls, differentiated into neurons were used. It was hypothesize that mitochondrial dysfunction causes a microtubule network disruption through the activation of cytosolic SIRT2. This event leads to the decreased efficiency of autophagic-lysosomal pathway (ALP), which, in turn, favors Abeta production. It was observed that mitochondria from AD and MCI groups present reduced membrane potential, are fragmented and its biogenesis is compromised. It was also observed an alteration in mitochondrial mediated redox signalling with an overactivation of SIRT2 and a decrease in acetylated-tubulin levels. These events disrupted microtubule-dependent intracellular traffic in AD cells which potentiated the accumulation of damaged, dysfunctional mitochondria within autophagosomes. Interestingly, it was found that despite MCI cybrids containing abnormal mitochondria, the functional threshold was not reached since microtubule integrity is maintained and ALP is over-activated. MCI cells are still able to degrade dysfunctional mitochondria since there is no evident accumulation of mitochondrial proteins, in opposition to AD cells. Overall, as many of the changes observed in AD cells are also seen in AD subject brains, it can be conclude that cumulative alterations in mitochondrial function, present in very early AD stages, leads to synaptic dysfunction and neuronal loss when microtubule assembly becomes compromised.