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P2‐128: Mitochondrion‐dependent oxidative stress in the context of neurodegeneration and cancer: Recent advance
Author(s) -
Aliev Gjumrakch,
Obrenovich Mark,
Bragin Valentin
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.833
Subject(s) - neurodegeneration , mitochondrion , biology , lipofuscin , oxidative stress , mitochondrial dna , pathology , cancer , in situ hybridization , microbiology and biotechnology , endocrinology , medicine , disease , biochemistry , genetics , gene , messenger rna
Background: Evidence suggests that functional as well as morphological alterations in size, shape and distribution of mitochondria are precipitating, early events in the progression of Alzheimer’s disease (AD).We have previously reported that a 20-22 kDa NH 2 -tau fragment (aka NH 2 htau), mapping between 26 and 250 aminoacids of the longest full length tau isoform, is detected in cellular and animal AD models and is neurotoxic in primary cultured neurons. The NH 2 htau -but not the physiological full-length proteinpreferentially interacts with Ab peptide(s) peptide(s) at human AD synapses and cooperates with it in inhibiting the ANT-1-dependent ADP/ATP exchange in mitochondria. Methods: Primary neuronal culture, adenovirusmediated infection, Western Blotting, immunocitochemistry, neuronal viability, citrate synthase and cytochrome c oxidase activities, GSH/GSSG ratio. Results: Here we report that the NH 2 htau fragment causes, in primary hippocampal neurons, an increased mitochondria fragmentation that mirrors in vivo changes in AD. The NH 2 htau also alters the organelle distribution with large numbers of small and defective mitochondria accumulating mainly in soma of dying neurons. An abnormal mitochondrial biogenesis/dynamism with a net mitochondrial loss/removal occurs in NH 2 htau fragment-expressing neurons and an early accumulation of autophagic vesicles correlates with the in vitro synaptic pathology. The specific disruption of mitochondrial morphology caused by NH 2 htau fragment is connected with a significant change in respiration and reactive oxygen species. Suppression of autophagy provides partial protection against the NH 2 htau fragment-induced neuronal death. Conclusions: The NH 2 htau affects the interplay between the mitochondria dynamism (fusion/fission) and the autophagic clearance (selective mitophagy). These results suggest that NH2htau can contribute to the mitochondrial dysfunction at human AD synapses not only by inhibiting the ANT-1-dependent ADP/ATP exchange but also, indirectly, by impairing the quality control mechanism of the organelle.