Mitochondrial Proteome Changes Correlating with β-Amyloid Accumulation

Abstract

Alzheimer's disease (AD) is a multifactorial disease of wide clinical heterogenity. Overproduction of amyloid precursor protein (APP) and accumulation of β-amyloid (Aβ) and tau proteins are important hallmarks of AD. The identification of early pathomechanisms of AD is critically important for discovery of early diagnosis markers. Decreased brain metabolism is one of the earliest clinical symptoms of AD that indicate mitochondrial dysfunction in the brain. We performed the first comprehensive study integrating synaptic and non-synaptic mitochondrial proteome analysis (two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry) in correlation with Aβ progression in APP/PS1 mice (3, 6, and 9 months of age). We identified changes of 60 mitochondrial proteins that reflect the progressive effect of APP overproduction and Aβ accumulation on mitochondrial processes. Most of the significantly affected proteins play role in the mitochondrial electron transport chain, citric acid cycle, oxidative stress, or apoptosis. Altered expression levels of Htra2 and Ethe1, which showed parallel changes in different age groups, were confirmed also by Western blot. The common regulator bioinformatical analysis suggests the regulatory role of tumor necrosis factor (TNF) in Aβ-mediated mitochondrial protein changes. Our results are in accordance with the previous postmortem human brain proteomic studies in AD in the case of many proteins. Our results could open a new path of research aiming early mitochondrial molecular mechanisms of Aβ accumulation as a prodromal stage of human AD.

Highly potent intracellular membrane-associated Aβ seeds

“…Our data are not the first to suggest an association of Aβ with mitochondrial or associated membrane structures. Aβ generation in MAMs and alterations of MAMs in neurons and synapses in AD and APP transgenic mice have been previously reported23242526 and an increased association of MAM and ER compartments have been suggested as a common denominator underlying AD pathogenesis27. Moreover, in yeast aggregated proteins were found tightly associated with mitochondria that in turn restrict aggregate mobility21.…”

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…In addition, neurons are exceedingly compartmentalized, comprising structures like: cell body, axon, dendrites and even more specific compartments that are the synapses, which makes a proper mitochondrial distribution pivotal to sustaining the energy requirement at specific locations within the different neuronal compartments [31,35,36]. The crucial role of mitochondria in supporting synaptic function and the concomitant occurrence of impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess of mitochondrial ROS generation and release with mediating synaptic transmission deregulation in AD seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD [32][33][34]37,41,43,47].…”

“…Evidence is presented suggesting amyloid oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, additional cofactors are required [13]. Those cofactors include several subcellular processes including oxidative damage [10,[14][15][16][17][18][19][20][21][22][23], recruitment of peripheral immune cells and excessive production of pro-inflammatory mediators [10,[24][25][26][27][28][29], mitochondrial impairments and chronic energy imbalance [12,20,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], chronic endoplasmic reticulum (ER) stress [48] and autophagy dysfunction [22,[49][50][51][52][53][54], the abnormality and dysfunction of MAM (the mitocho...…”

Metabolic study of Alzheimer’s disease using mutant C. elegans

“…How glucose energy metabolism regulates AD progression is still under investigation. It is well known that both Aβ and NFTs impair mitochondrial functions [29,30]. Suppression of glucose energy metabolism (oxidative phosphorylation) showed reduction in Aβ toxicity in model systems as well as in neuronal cell lines [31,32] whereas, increase in oxidative phosphorylation was found to enhance the Aβ toxicity [33].…”

“…The presence of Aβ in mice and neuronal cell lines causes mitochondrial dysfunction by inducing mitochondrial DNA damage, disrupting mitochondrial redox potential and inducing oxidative stress [29,[440][441][442]. Exposure to 2-deoxy-d-glucose (2DOG), which is an analogue of glucose that inhibits both glycolysis and oxidative phosphorylation, causes a decrease in Aβ toxicity [31,32].…”