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Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the upregulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward ␤-amyloid (A␤) peptide insult, suggesting a synergistic action of tau and A␤ pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by A␤. Alzheimer disease (AD)1 is characterized by two major histopathological hallmarks, extracellular plaques of fibrillar ␤-amyloid (A␤) peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (1, 2). Mutations in tau have been identified in a related neurodegenerative disorder called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with NFT formation in the absence of plaque formation (3-5). Transgenic mice overexpressing the P301L mutant human tau protein were created to model tauopathies in vivo (6, 7). These mice show an accumulation of hyperphosphorylated tau and NFT formation similar to those in FTDP-17 and AD.Little is known about the distinct intracellular mechanisms underlying the consequences of tau pathology. This insight could help us to understand the selective vulnerability of cells with tau pathology and thereby the pathogenesis of AD. Increasing evidence highlights a connection between AD and mitochondrial dysfunction together with a deregulation of energy metabolism and oxidative stress (8). Various reports have demonstrated markedly reduced levels of mitochondrial proteins and activities (9 -11), decreased glucose turnover (12, 13), increased mitochondrial DNA mutations (14 -16), and increased lipid peroxidation (17-19) in AD brains.To examine the contribution of tau to these neurodegenerative processes, we carried out a proteomic analysis of our P301L tau transgenic mice. To zoom in on proteins relevant to the p...

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 ␤ (A␤) 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 A␤ levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular A␤ production by a functional ␥-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of A␤ in these processes. Extracellular treatment of PC12 cells with comparable A␤ concentrations only leads to weak changes, demonstrating the important role of intracellular A␤. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable A␤ 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 A␤ 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.

With the increasing average life span of humans and with decreasing cognitive function in elderly individuals, age-related cognitive disorders including dementia have become a major health problem in society. Aging-related mitochondrial dysfunction underlies many common neurodegenerative disorders diseases, including Alzheimer's disease (AD). AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein. In this review, the authors focus on the latest findings in AD animal models indicating that these histopathological alterations induce deficits in the function of the complexes of the respiratory chain and therefore consecutively result in mitochondrial dysfunction. This parameter is intrinsically tied to oxidative stress. Both are early events in aging and especially in the pathogenesis of aging-related severe neurodegeneration. Ginkgo biloba extract seems to be of therapeutic benefit in the treatment of mild to moderate dementia of different etiology, although the data are quite heterogeneous. Herein, the authors suggest that mitochondrial protection and subsequent reduction of oxidative stress are important components of the neuroprotective activity of Ginkgo biloba extract.

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We recently provided evidence for a mitochondrial dysfunction in P301L tau transgenic mice, a strain modeling the tau pathology of Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition to tau aggregates, the AD brain is further characterized by Aβ peptide-containing plaques. When we addressed the role of Aβ, this indicated a synergistic action of tau and Aβ pathology on the mitochondria. In the present study, we compared the toxicity of different Aβ42 conformations in light of recent studies suggesting that oligomeric rather than fibrillar Aβ might be the actual toxic species. Interestingly, both oligomeric and fibrillar, but not disaggregated (mainly monomeric) Aβ42 caused a decreased mitochondrial membrane potential in cortical brain cells obtained from FTD P301L tau transgenic mice. This was not observed with cerebellar preparations indicating selective vulnerability of cortical neurons. Furthermore, we found reductions in state 3 respiration, the respiratory control ratio, and uncoupled respiration when incubating P301L tau mitochondria either with oligomeric or fibrillar preparations of Aβ42. Finally, we found that aging specifically increased the sensitivity of mitochondria to oligomeric Aβ42 damage indicating that oligomeric and fibrillar Aβ42 are both toxic, but exert different degrees of toxicity.

Background: Mitochondrial dysfunction has been identified in neurodegenerative disorders including Alzheimer’s disease, where accumulation of β-amyloid (Aβ) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction. Objective: In order to study the in vivo effect of Aβ load during aging, we evaluated the mitochondrial function of brain cells from transgenic mice bearing either mutant amyloid precursor protein (tgAPP) or mutant amyloid precursor protein and mutant PS1 (tgAPP/PS1) as well as from nontransgenic wild-type littermates. tgAPP mice exhibit onset of Aβ plaques at an age of 6 months, but the intracellular soluble Aβ load is already increased at 3 months of age. In contrast, onset of Aβ plaques starts at an age of 3 months in tgAPP/PS1 mice. In addition, we investigated the effects of different Aβ preparations on mitochondrial function of brain cells from tau transgenic mice. Results: Of note, mitochondrial damage such as reduced mitochondrial membrane potential and ATP levels can already be detected in the brains from these mice before the onset of plaques. In agreement with our findings in tgAPP mice, soluble Aβ induced mitochondrial dysfunction in brain cells from tau transgenic mice. Conclusion: Our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble Aβ species as a very early event during pathogenesis.

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