Mitochondrial dysfunction induced by disease relevant AbetaPP and tau protein mutations.

Alzheimer's disease is characterized by two major pathological hallmarks: extracellular plaques consisting of amyloid beta peptide and neurofibrillary tangles composed of hyperphosphorylated tau protein. Mutations in the amyloid beta-protein precursor (AbetaPP) have been linked to familial Alzheimer's disease. They are leading to increased amyloid beta production. Mutations in the tau gene have not been described in AD, but are leading to formation of neurofibrillary tangles very similar to filaments in AD brains, and are therefore of increasing relevance in AD research. Interestingly, our data indicate that mutations in AbetaPP gene and mutations in tau gene induce mitochondrial dysfunction and oxidative stress in cell culture models and transgenic mice. Thus, both Alzheimer relevant protein alterations seem to have synergistic actions probably at the level of mitochondria leading to synaptic dysfunction and apoptotic cell death.

Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease.

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of many common age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common neurodegenerative disorder characterized by dementia, memory loss, neuronal apoptosis and eventually death of the affected individuals. AD is characterized by two pathologic hallmark lesions that consist of extracellular plaques of amyloid-beta peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau. Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein and tau alterations in this type of dementia remains controversial.

Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis.

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease. Thus, we investigated the effects of acute and chronic exposure to increasing concentrations of amyloid beta (Abeta) on mitochondrial function and nitric oxide (NO) production in vitro and in vivo. Our data demonstrate that PC12 cells and human embryonic kidney cells bearing the Swedish double mutation in the amyloid precursor protein gene (APPsw), exhibiting substantial Abeta levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular Abeta production by a functional gamma-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of Abeta in these processes. Extracellular treatment of PC12 cells with comparable Abeta concentrations only leads to weak changes, demonstrating the important role of intracellular Abeta. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable Abeta levels in the brain, reduced ATP levels can also be observed showing the in vivo relevance of our findings. Moreover, we could demonstrate that APP is present in the mitochondria of APPsw PC12 cells. This presence might be directly involved in the impairment of cytochrome c oxidase activity and depletion of ATP levels in APPsw PC12 cells. In addition, APPsw human embryonic kidney cells, which produce 20-fold increased Abeta levels compared with APPsw PC12 cells, and APP tg mice already show a significantly decreased mitochondrial membrane potential under basal conditions. We suggest a hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction finally leading to cell death.

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease.

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer's disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Abeta) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Abeta production with mitochondrial dysfunction, caspase pathway, and neuronal loss.

Neurotoxic mechanisms caused by the Alzheimer's disease-linked Swedish amyloid precursor protein mutation: oxidative stress, caspases, and the JNK pathway.

Autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the beta-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.