Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

Eckert, Anne; Schmitt, Karen; Götz, Jürgen

doi:10.1186/alzrt74

Cited by 150 publications

(120 citation statements)

References 69 publications

(97 reference statements)

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“…A mass spectrometric analysis of the brain proteins from these mice revealed mainly a deregulation of mitochondrial respiratory chain complex components (including complex V), antioxidant enzymes, and synaptic protein space (11). The reduction in mitochondrial complex V levels in the P301L tau mice that was revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (FTD with parkinsonism linked to chromosome 17) brains. The functional analysis demonstrated age-related mitochondrial dysfunction, together with reduced NADHubiquinone oxidoreductase (complex I) activity as well as age-related impaired mitochondrial respiration and ATP synthesis in pR5 mice model.…”

Section: Separate Modes Of Ab and Tau Toxicity On Mitochondriamentioning

confidence: 82%

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Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Schmitt

Grimm

Kaźmierczak

et al. 2012

Antioxidants & Redox Signaling

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123

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Significance: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder mainly affecting elderly individuals. The pathology of AD is characterized by amyloid plaques (aggregates of amyloid-b [Ab]) and neurofibrillary tangles (aggregates of tau), but the mechanisms underlying this dysfunction are still partially unclear. Recent Advances: A growing body of evidence supports mitochondrial dysfunction as a prominent and early, chronic oxidative stress-associated event that contributes to synaptic abnormalities and, ultimately, selective neuronal degeneration in AD. Critical Issues: In this review, we discuss on the one hand whether mitochondrial decline observed in brain aging is a determinant event in the onset of AD and on the other hand the close interrelationship of this organelle with Ab and tau in the pathogenic process underlying AD. Moreover, we summarize evidence from aging and Alzheimer models showing that the harmful trio ''aging, Ab, and tau protein'' triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation (OXPHOS), elevation of reactive oxygen species production, and interaction with mitochondrial proteins, contributing to the development and progression of the disease. Future Directions: The aging process may weaken the mitochondrial OXPHOS system in a more general way over many years providing a basis for the specific and destructive effects of Ab and tau. Establishing strategies involving efforts to protect cells at the mitochondrial level by stabilizing or restoring mitochondrial function and energy homeostasis appears to be challenging, but very promising route on the horizon.

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Section: Separate Modes Of Ab and Tau Toxicity On Mitochondriamentioning

confidence: 82%

“…Within the past years, several mouse models have been developed that reproduce the aging process and diverse aspects of AD. These models help in understanding the age-related pathogenic mechanisms that lead to mitochondrial failure in AD, and in particular the interplay of AD-related cellular modifications within this process (17,18).…”

Section: Introductionmentioning

confidence: 99%

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Schmitt

Grimm

Kaźmierczak

et al. 2012

Antioxidants & Redox Signaling

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123

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“…These findings are summarized in recent review articles, therefore suggesting that Aβ is responsible for the induction of mitochondrial dysfunction typically observed in AD ( Fig. 1) [10][11][12].…”

Section: Introductionmentioning

confidence: 76%

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

Benek¹,

Aitken²,

Hroch³

et al. 2015

CMC

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Abstract:The amyloid-β peptide (Aβ) has been associated with Alzheimer's disease (AD) for decades. The original amyloid cascade hypothesis declared that the insoluble extracellular plaques were responsible for Aβ toxicity. Later, this hypothesis has been updated and soluble intracellular Aβ forms and their effects within the cell have come into focus. Mitochondrial dysfunction plays an important role in the pathophysiology of AD. Aβ was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aβ. Such interactions can affect a protein's function and cause damage to the mitochondria and finally to the whole cell. This review summarizes the current knowledge of mitochondrial proteins directly interacting with Aβ and discusses their significance for the development of therapeutics in the treatment of AD.

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“…Several studies have identified structural and functional mitochondrial abnormalities in hippocampal neurones of AD patients compared with age-and sex-matched controls [213][214][215][216]. Such abnormalities include a significant reduction in mitochondrial numbers and exaggerated levels of oxidised mitochondrial DNA (mtDNA) and nitrated proteins in the cytoplasm in a pattern suggestive of impaired mitophagy or fission dynamics [215][216][217]. These mitochondrial abnormalities are accompanied by oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine, indicating that the mitochondria are damaged by ROS and RNS during disease progression [213,218,219].…”

Section: Oxidative Stress and The Development Of Mitochondrial Dysfunmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

Cited by 150 publications

References 69 publications

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

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Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity

Cited by 150 publications

References 69 publications

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

Insights into Mitochondrial Dysfunction: Aging, Amyloid-β, and Tau–A Deleterious Trio

A Direct Interaction Between Mitochondrial Proteins and Amyloid-&#946; Peptide and its Significance for the Progression and Treatment of Alzheimer&#8217;s Disease

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

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A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease