Susanne Hauptmann

University Hospital Frankfurt, Frankfurt, Hesse, Germany

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Publications (13)51.11 Total impact

  • Focus on Alternative and Complementary Therapies 01/2010; 9:34-35.
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    ABSTRACT: 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.
    Journal of Molecular Medicine 10/2008; 86(11):1255-1267. · 4.77 Impact Factor
  • European Psychiatry 04/2008; 23. · 3.29 Impact Factor
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    ABSTRACT: Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Ass) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Ass pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Ass deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Ass. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Ass dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Ass and progression accelerates substantially with aging.
    Neurobiology of aging 03/2008; 30(10):1574-86. · 5.94 Impact Factor
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    ABSTRACT: Mitochondrial dysfunction has been identified in neurodegenerative disorders including Alzheimer's disease, where accumulation of beta-amyloid (Abeta) 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 Abeta 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 Abeta plaques at an age of 6 months, but the intracellular soluble Abeta load is already increased at 3 months of age. In contrast, onset of Abeta plaques starts at an age of 3 months in tgAPP/PS1 mice. In addition, we investigated the effects of different Abeta preparations on mitochondrial function of brain cells from tau transgenic mice. 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 Abeta induced mitochondrial dysfunction in brain cells from tau transgenic mice. Our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble Abeta species as a very early event during pathogenesis.
    Neurodegenerative Diseases 02/2008; 5(3-4):157-9. · 3.41 Impact Factor
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    ABSTRACT: 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.
    Pharmacological Research 01/2008; 56(6):493-502. · 4.35 Impact Factor
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    ABSTRACT: 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.
    Antioxidants and Redox Signaling 11/2007; 9(10):1659-75. · 7.19 Impact Factor
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    ABSTRACT: 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.
    Journal of Alzheimer's disease: JAD 08/2006; 9(2):139-46. · 4.17 Impact Factor
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    ABSTRACT: 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.
    Experimental Gerontology 08/2006; 41(7):668-73. · 3.91 Impact Factor
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    ABSTRACT: 1.--Mitochondrial dysfunction including decrease of mitochondrial membrane potential and reduced ATP production represents a common final pathway of many conditions associated with oxidative stress, for example, hypoxia, hypoglycemia, and aging. 2.--Since the cognition-improving effects of the standard nootropic piracetam are usually more pronounced under such pathological conditions and young healthy animals usually benefit little by piracetam, the effect of piracetam on mitochondrial dysfunction following oxidative stress was investigated using PC12 cells and dissociated brain cells of animals treated with piracetam. 3.--Piracetam treatment at concentrations between 100 and 1000 microM improved mitochondrial membrane potential and ATP production of PC12 cells following oxidative stress induced by sodium nitroprusside (SNP) and serum deprivation. Under conditions of mild serum deprivation, piracetam (500 microM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. 4.--Piracetam treatment (100-500 mg kg(-1) daily) of mice was also associated with improved mitochondrial function in dissociated brain cells. Significant improvement was mainly seen in aged animals and only less in young animals. Moreover, the same treatment reduced antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and glutathione reductase) in aged mouse brain only, which are elevated as an adaptive response to the increased oxidative stress with aging. 5.--In conclusion, therapeutically relevant in vitro and in vivo concentrations of piracetam are able to improve mitochondrial dysfunction associated with oxidative stress and/or aging. Mitochondrial stabilization and protection might be an important mechanism to explain many of piracetam's beneficial effects in elderly patients.
    British Journal of Pharmacology 02/2006; 147(2):199-208. · 5.07 Impact Factor
  • Article: P4-001
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2006; 2(3).
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    ABSTRACT: 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.
    Annals of the New York Academy of Sciences 12/2005; 1056:474-85. · 4.38 Impact Factor
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    ABSTRACT: 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 dys-function 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 up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.
    Journal of Biological Chemistry 07/2005; 280(25):23802-14. · 4.65 Impact Factor