Focus on Alternative and Complementary TherapiesVolume 9, Issue s1 p. 34-35 Stabilisation of mitochondrial membrane potential by Ginkgo biloba EGb 761 WE Müller, WE Müller Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorU Keil, U Keil Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorI Scherping, I Scherping Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorS Hauptmann, S Hauptmann Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorA Eckert, A Eckert Department of Neurobiology, Psychiatric University of Basel, Basel, CH-4025, SwitzerlandSearch for more papers by this author WE Müller, WE Müller Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorU Keil, U Keil Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorI Scherping, I Scherping Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorS Hauptmann, S Hauptmann Department of Pharmacology, Biocenter, University of Frankfurt, Frankfurt, D-60439, GermanySearch for more papers by this authorA Eckert, A Eckert Department of Neurobiology, Psychiatric University of Basel, Basel, CH-4025, SwitzerlandSearch for more papers by this author First published: 14 June 2010 https://doi.org/10.1111/j.2042-7166.2004.tb04540.xCitations: 1Read the full textAbout ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume9, Issues1March 2004Pages 34-35 RelatedInformation

We recently provided evidence for a mitochondrial dysfunction in P301 L 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 P301 L 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 P301 L 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.

cells 250 Caenorhabditis elegans 182 Cell signaling 146 Cerebrospinal fluid markers 133 Cholesterol 212 Choline acetyltransferase 228 Cholinergic basal forebrain 228 -system 225 Cleavage precision 160

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.

A large body of data emphasizes the central role of mitochondrial dysfunction during aging and as an early event in neurodegenerative diseases. In this study we used PC12 cells and dissociated mice brain cells, as well as isolated mitochondria to investigate the effects of EGb 761 on mitochondrial functions. We mimicked mitochondrial abnormalities during aging by using external factors (nitrosative stress, serum deprivation and complexes inhibitors) consequently altering mitochondrial processes, such as energy metabolism. As markers for the function of mitochondria, ATP levels and mitochondrial membrane potential were measured. EGb 761 alleviated mitochondrial functions in vitro at concentrations as low as 0.01 mg/ml. Treating two different age groups of mice with EGb 761 (100mg/kg body weight for 14 days) showed beneficial effects on complexes I, IV and V of the mitochondrial respiratory chain and against nitrosative stress. Interestingly, these effects were only observed in the aged mice group, proving higher efficacy of EGb 761 during aging. The single components of EGb 761 showed in both cell models protection of the mitochondrial membrane potential indicating that a complementary action of the components is responsible for the versatile actions of EGb 761.

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-β 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.

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 has been identified in neurodegenerative disorders including Alzheimer's disease (AD), where accumulation of amyloid beta (A beta) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction. In order to study the in vivo effect of A beta load during aging, we evaluated the mitochondrial function of brain cells from transgenic (tg) mice bearing mutant amyloid precursor protein (APP, Swedish and London mutation) and non–tg littermate control animals (non–tg) at different ages (1.5, 3, and 6 months). TgAPP mice exhibit onset of A beta plaques at an age of 6 months, but intracellular soluble A (beta) load is already increased at the age of 3 months. In addition, we investigated the effects of different A beta species on mitochondrial function of brain cells from tau transgenic mice. Basal mitochondrial transmembrane potential was already decreased in tgAPP mice at an age of 1.5 months and decreased further with aging. ATP levels were significantly reduced in tgAPP mice at an age of 3 months compared to age–matched non–tg control mice. Interestingly, cytochrome c oxidase activity was markedly reduced in tgAPP mice at an age of 1.5 and 3 months. The difference was less pronounced at an age of 6 months. In agreement with our findings in tgAPP, soluble A beta oligomers induced mitochondrial dysfunction in brain cells from tau transgenic mice. Interestingly, this effect was only present in cortical brain cells, but not in cerebellum. Taken together, our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble A beta species as a very early event during pathogenesis.

Ginkgo biloba extract EGb 761 has been used for many years to treat age-related cognitive disorders including Alzheimer's disease. EGb 761 given shortly after initiating mitochondrial damage by sodium nitroprusside (nitric oxide donor) improved the mitochondrial membrane potential of PC12 cells significantly and dose dependently. Under these conditions, EGb 761 also reversed the decrease in ATP production. In addition, similar protection against oxidative damage was found in dissociated brain cells and isolated brain mitochondria after in vitro or in vivo treatment with EGb 761. Moreover, PC12 cells bearing an Alzheimer's disease-related mutation in the amyloid precursor protein, which leads to enhanced beta amyloid production, showed greater benefit from treatment with EGb 761 than did control cells. Taken together, our findings clearly show stabilization and protection of mitochondrial function as a specific and very sensitive property of EGb 761 at therapeutically relevant doses.

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease. Thus, we investigated 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 HEK cells bearing the Swedish double mutation in the amyloid precursor protein (APPsw), exhibiting substantial A levels, have increased NO levels and reduced ATP levels already under basal conditions. 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 tg mice, which exhibit no plaques but already detectable A levels in the brain, the reduced ATP levels can also be observed showing the in vivo relevance of our findings. Moreover, we could demonstrate that APP is accumulated in mitochondria of APPsw PC12 cells. This accumulation might be directly involved in the impairment of cytochrome C oxidase activity and depletion of ATP levels in APPsw PC12 cells. In addition, a pronounced decrease in mitochondrial membrane potential and increased Smac release in APPsw PC12 cells compared to control cells can be observed after secondary insult. APPsw HEK cells, which produce 30-fold increased A levels compared to APPsw PC12 cells, and 3-monthold APP tg mice show already under basal conditions a significantly decreased mitochondrial membrane potential. Based on our findings, we suggest a hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction.