Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease

Hauptmann, Susanne; Keil, Uta; Scherping, Isabel; Bonert, Astrid; Eckert, Anne; Müller, Wernér E.G.

doi:10.1016/j.exger.2006.03.012

Cited by 111 publications

(71 citation statements)

References 44 publications

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“…We also provided first evidence for an increased vulnerability of P301L tau mitochondria towards fibrillar Aβ insult, suggesting a synergistic action of tau and Aβ pathology on the mitochondria [19][20][21].…”

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confidence: 58%

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

et al. 2008

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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.

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confidence: 58%

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

et al. 2008

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“…Failure of ATP synthase could contribute to a decrease in the activity of the entire ETC and impaired ATP production, resulting in possible electron leakage and increased ROS production, suggesting an alternate rationale for the OS seen in AD (10,74). Altered expression of mitochondrial proteins, functional deficits, and lowered activity in different complexes of the ETC are observed in AD (184,281). These changes, coupled with the changes in complex I, III, and IV, may cause electron leakage from the mitochondria to produce ROS.…”

Section: Identification Of Carbonylated Proteins In Brainmentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

153

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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“…Mitochondrial dysfunction may be an early event in the pathogenesis of AD [121][122][123]. AD patients show impairments in mitochondrial function that start early in process of neurodegeneration [121,123].…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…AD patients show impairments in mitochondrial function that start early in process of neurodegeneration [121,123]. Mutations in the AbetaPP and tau genes induce oxidative stress and mitochondrial dysfunction leading eventually to apoptotic cell death [124].…”

Section: Alzheimer's Disease (Ad)mentioning

confidence: 99%

Neurodegenerative and Fatiguing Illnesses, Infections and Mitochondrial Dysfunction: Use of Natural Supplements to Improve Mitochondrial Function.

Nicolson

Settineri

Ellithorpe³

2014

FFHD

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Background: Many chronic diseases and illnesses are associated with one or more chronic infections, dysfunction of mitochondria and reduced production of ATP. This results in fatigue and other symptoms that occur in most if not all chronic conditions and diseases.Methods: This is a review of the published literature on chronic infections in neurodegenerative diseases and fatiguing illnesses that are also typified by mitochondrial dysfunction. This contribution also reviews the use of natural supplements to enhance mitochondrial function and reduce the effects of chronic infections to improve overall function in various chronic illnesses.Results: Mitochondrial function can be enhanced by the use of various natural supplements, notably Lipid Replacement Therapy (LRT) using glyerolphospholipids and other mitochondrial supplements. In various chronic illnesses that are characterized by the presence of chronic infections, such as intracellular bacteria (Mycoplasma, Borrelia, Chlamydia and other infections) and viruses, LRT has proven useful in multiple clinical trials. For example, in clinical studies on chronic fatigue syndrome, fibromyalgia syndrome and other chronic fatiguing illnesses where a large majority of patients have chronic infections, LRT significantly reduced fatigue by 35-43% in different clinical trials and increased mitochondrial function. In clinical trials on patients with multiple intracellular bacterial infections and intractable fatigue LRT plus other mitochondrial supplements significantly decreased fatigue and improved mood and cognition.Conclusions: LRT formulations designed to improve mitochondrial function appear to be useful as non-toxic dietary supplements for reducing fatigue and restoring mitochondrial and other cellular membrane functions in patients with chronic illnesses and multiple chronic infections. BackgroundPatients with chronic neurodegenerative, neurobehavioral and fatiguing illnesses commonly test positive for systemic and central nervous system (CNS) bacterial and viral infections [1][2][3]. In addition, other chronic illnesses where neurological manifestations are routinely found, such as autoimmune diseases and other chronic illnesses and disorders, also show evidence of systemic bacterial and viral infections that could be important in disease inception, progression and/or enhancing the types and severities of signs and symptoms [2,3].Evidence of bacterial infections, such as Mycoplasma species, Chlamydia pneumoniae, Borrelia burgdorferi, among others, and viruses, such as human herpesvirus (HHV), cytomegalovirus (CMV), human herpes viruses (HHV) and other viral infections, have revealed high rates of infection in the illnesses listed above that were not found in control populations [1][2][3]. Although the specific roles of chronic infections in various diseases and their pathogeneses have not been carefully determined, the data suggest that chronic bacterial and/or viral infections are common features of essentially all progressive chronic diseases [1][2][3].An...

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Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease

Cited by 111 publications

References 44 publications

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

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

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Neurodegenerative and Fatiguing Illnesses, Infections and Mitochondrial Dysfunction: Use of Natural Supplements to Improve Mitochondrial Function.

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