Mitochondrial dysfunction and AD

The role of mitochondria in aging and neurodegenerative diseases has received much more attention in the last decade. Due to the present evidence nowadays, mitochondrial dysfunction is believed to play a pivotal role in aging and AD.

Simply, mitochondria are double-membranous, self-replicating organelles with a circular genome of 16.5 kb DNA (Chen and Chan 2005). They are essential for cell viability and functioning. Mitochondria contain their own mitochondrial DNA and machinery for transcription, translation, and protein assembly. The mitochondrial DNA codes for 13 polypeptides that are part of the mitochondrial electron-transport chain, which is involved in the oxidative phosphorylation that generates adenosine triphosphate [ATP]. The production of ATP [energy] is the major function of the mitochondria and this is why they are known as power house of the cell. Oxidative phosphorylation operates through five protein complexes embedded in the inner membrane of the mitochondria known as respiratory chain complexes [see figure 1-12].

Since neuronal functions and synaptic neurotransmission require vast amounts of energy, mitochondria occupy an essential task by generating ATP and maintaining calcium homeostasis (Nicholls and Budd 2000;Kann and Kovacs 2007). Therefore, impairment in mitochondrial vital functions may have serious and deleterious consequences on neuronal physiology.

Figure 1-12

Diagram showing mitochondria and the respiratory chain

Researchers have in the last few years found many evidences linking mitochondrial dysfunction to AD. Baloyannis reviewed the morphologic alterations of the mitochondria in 22 brains of AD patients, and reported disruption of the cristae and/or osmiophilic inclusions (Baloyannis 2006).

Morphometric studies of the mitochondria in AD revealed a significant reduction in mitochondria density in endothelial cells as well as in fibroblasts obtained from patients with AD (Stewart et al. 1992).This observation was also seen in mitochondria from Frontal and temporal cortex of AD patients (Hirai et al. 2001).

Not only morphological changes in AD mitochondria were noticed but more importantly functional changes. Positron emission tomography [PET] showed decrease energy metabolism in AD brains (Azari et al. 1993;Grady et al.

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is the main pathway for oxidation of glucose in the brain. Deficiency in the two key enzymes of the rate-limiting step of the TCA cycle, Pyruvate dehydrogenese [PDHC] and alpha -ketoglutarate dehydrogenase complex, [KGDHC] has been documented in AD cases by multiple groups, suggesting defects in glucose metabolism in the AD brains (Gibson et al. 2000;Sorbi et al. 1983). Normally, electrons from the TCA are transported across the respiratory chain in order to produce ATP. Deficiency of cytochrome-c-oxidase [COX] [complex IV of the respiratory chain] in different AD brain regions has been reported (Bosetti et al. 2002;Mutisya et al. 1994). So it seems that COX and most probably PDHC and KGDHC activities are decreased in AD patients, the exact mechanism of their deactivation is not known but interestingly it has been reported that Aß inhibits both COX and KGDHC in isolated brain mitochondria (Casley et al. 2002).

Aß seems also to have other toxic effects on the mitochondria in cell and animal models. Previous studies showed that in the presence of Ca⁺² Aß 40 and Aß25–35 induce the opening of Permeability transition pore [PTP]

(Mancuso et al. 2006;Mancuso et al. 2003). PTP induction, a phenomenon characterized by a sudden increase in the permeability of the inner mitochondrial membrane, plays a key role in apoptotic cell death by facilitating the release of apoptogenic factors.

The toxic effects of Aß on the mitochondria were observed in transgenic animal models as well, for example Keil et al demonstrated a decrease in mitochondrial membrane potential and ATP levels in APP-transgenic mouse when compared to littermate non-transgenic mice. Accumulation of Aß in Tg2576 AD transgenic mice and mouse neuroblastoma cells expressing human APP correlated with high levels of H2O2, impaired cytochrome-oxidase activity, and increased carbonylation of mitochondrial proteins (Manczak et al. 2006).

Anandatheerthavarada et al linked amyloid to the mitochondrion. These authors showed, for the first time, that APP is targeted to neuronal mitochondria. They showed in a transgenic mouse model of AD [Tg2576]

that over-expresses Swedish APP, accumulation of incompletely translocated full-length APP in the mitochondrial compartment of the cortex and hippocampus known to be affected in AD (Anandatheerthavarada et al. 2003).

The same group then extended their results in human AD brains. They found that non-glycosylated full-length and C-terminally–truncated APP was associated with mitochondria in samples from the brains of individuals with AD, but not with mitochondria in samples from non-demented subjects (Devi et al. 2006). However, the frontal cortex, hippocampus, and amygdala showed the highest accumulation of APP in the mitochondria of all three categories of AD brains. Triple-labeling immuno-histochemistry of AD brains revealed the accumulation of APP in the mitochondria of cholinergic neurons of all stages of AD brains.

In order to study more extensively the effect of mitochondria in AD the cytoplasmic hybrid (“cybrid”) technique, first described in 1989 (King and Attardi 1989), has been applied. In this technique, mitochondria/ mtDNA from human AD and control platelets is transferred to cultivable cells depleted of endogenous mtDNA. Interestingly the AD cybrids showed elevated secretion of Aß, they also confirmed the COX deficiency found in the mitochondria of AD patients. AD cybrids also show elevated spontaneous death with apoptotic nuclear morphology and decrease in mitochondrial membrane potential (Khan et al. 2000). Moreover, increased caspase-3 activity and elevated cleavage of caspase substrate were previously reported (Khan et al. 2000;Onyango et al. 2005).

Wrapping up this section, mitochondrial dysfunction is always involved in AD, whether present in post-mortem AD tissue, transgenic cell or animal

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AD plays a key role in mitochondrial impairment. However which starts first, Aβ aggregation or mitochondrial dysfunction in this viscous cycle is still an unanswered question.