Susanne Hauptmann

Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice.

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimers 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.

Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice

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.

Oligomeric and fibrillar species of β-amyloid (Aβ42) both impair mitochondrial function in P301L tau transgenic mice

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.

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 Alzheimers 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 Alzheimers disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein and tau alterations in this type of dementia remains controversial.

Stabilization of Mitochondrial Membrane Potential and Improvement of Neuronal Energy Metabolism by Ginkgo Biloba Extract EGb 761

Ginkgo biloba extract EGb 761 has been used for many years to treat age‐related cognitive disorders including Alzheimers 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 Alzheimers 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.

Piracetam improves mitochondrial dysfunction following oxidative stress

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. 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. Piracetam treatment at concentrations between 100 and 1000 μM 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 μM) induced a nearly complete recovery of mitochondrial membrane potential and ATP levels. Piracetam also reduced caspase 9 activity after SNP treatment. 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. 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 piracetams beneficial effects in elderly patients.

Mitochondrial dysfunction induced by disease relevant AβPP and tau protein mutations

Alzheimers 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 Alzheimers 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.

P4-001: Soluble amyloid-beta leads to mitochondrial failure in APP and tau transgenic mice

Background: Cholinesterase inhibitors, which are now the recommended treatment for patients with mild to moderate Alzheimer’s Disease have been in use since the late 1990’s. Most clinical drug trials using these drugs are short term with some long-term open-label extensions. Few long-term studies are done in clinical practice settings where patients may differ in clinical profile and ethnicity from those enrolled in clinical trials. Objective: This study aims to evaluate the efficacy of a cholinesterase inhibitor, donepezil, in patients with probable mild to moderate Alzheimer’s Disease in a clinical practice setting over a period of two years in an Asian population. Methods: This study was conducted in patients with Alzheimer’s Disease who were evaluated and treated at the St. Luke’s Memory Center in the Philippines. Thirty-nine patients were treated with Donepezil in accordance with approved product information (up to 10 mg/day). The medication was given open-label while independent raters blinded to treatment administered the cognitive tests. A responsible family caregiver for every patient was available to ensure compliance with the medications. Follow-up period was two years. Results: The mean age was 75.15 7.06, 82.1% were women, and 87.2% had mild dementia. The baseline Mini Mental State Examination (MMSE) was 19.41 4.91. Improvement from baseline MMSE was observed at 6 months (mean change of 2.04 points) and was sustained up to 12 months. Following this, decline below baseline assessments was observed at 1.5 years and with mean decline -0.63 at 2 years. Conclusion: This study showed that treatment with Donepezil delays cognitive decline up to one year and stabilizes cognitive function over a period of two years. The decline after 1 year is slower and later than expected of patients left untreated. The results are also consistent with findings reported in other ethnic populations.