March separate, strike together — Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease

Nisbet, Rebecca M.; Grimm, Amandine; Götz, Jürgen

doi:10.1016/j.bbadis.2013.08.013

Cited by 98 publications

(84 citation statements)

References 134 publications

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“…Under conditions of elevated tau, the delicate balance of fission and fusion is also deregulated. Fission is impaired and an elongated mitochondrial network results [85].…”

Section: Pathogenic Tau and Mitochondrial Transportmentioning

confidence: 99%

Axonal Transport Defects in Alzheimer’s Disease

Wang

Tan

2014

Mol Neurobiol

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A large body of evidences indicates that axonal transport (AT) defects play an important role in the pathogenesis of Alzheimer' disease (AD). AT, a critical cellular process for the maintenance and function of a neuron, requires components of the cytoskeletons as "tracks", motor proteins and ATP as "driving force", adaptor proteins to ensure the specific connection of the transported cargoes and motor proteins as well as active regulation. In AD pathology, AD-linked pathologic factors respectively perturb the four basic components of AT through different signaling pathways to cause AT defects. Mitochondrial transport, which is different from other transport cargoes, is also impaired via special pathways in AD. In this paper, we review the inhibitory effects of those factors on AT and their possible pathways, indicating these factors act in overlapping, synergistic, and circulating ways. Given the contributions of AT defects to AD, recent therapeutic studies focus on microtubule-stabilizing (MT-stabilizing) agents and alteration in phosphotransferase activities, and we propose more therapeutic strategies targeting AT defects.

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“…Under conditions of elevated tau, the delicate balance of fission and fusion is also deregulated. Fission is impaired and an elongated mitochondrial network results [85].…”

Section: Pathogenic Tau and Mitochondrial Transportmentioning

confidence: 99%

Axonal Transport Defects in Alzheimer’s Disease

Wang

Tan

2014

Mol Neurobiol

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“…Mitochondria serve two important physiological functions relevant to AD development: i) they provide the energy supply especially needed in the mitochondria-rich synapses of the brain, and ii) liberation of pro-apoptotic proteins from the mitochondrial intermembrane space into the cytoplasm, such as holo-cytochrome C, causes caspase activation and apoptotic cell death. It has been suggested that Aß peptides and hyperphosphorylated tau synergistically cause an increased mitochondrial production of reactive oxygen species (ROS), which damage mitochondrial membranes and mtDNA [45]. This leads to more dysfunctional mitochondria and thereby to more ROS production and oxidative stress, which in turn may increase tau phosphorylation and formation of Aß aggregates.…”

Section: Aging Energy Mitochondria and Oxidative Stressmentioning

confidence: 99%

“…Tau phosphorylation and aggregation is both triggered by and triggering itself mitochondrial dysfunctions [45]. Mitochondria serve two important physiological functions relevant to AD development: i) they provide the energy supply especially needed in the mitochondria-rich synapses of the brain, and ii) liberation of pro-apoptotic proteins from the mitochondrial intermembrane space into the cytoplasm, such as holo-cytochrome C, causes caspase activation and apoptotic cell death.…”

Section: Aging Energy Mitochondria and Oxidative Stressmentioning

confidence: 99%

“…A by-product of mitochondrial respiration are reactive oxygen species (ROS), whose concentration increase with age and mitochondrial malfunctions. While this leads to aggregation of both Aß and tau, in turn these two pathological hallmarks of AD have been proposed to cause mitochondrial malfunctions [45,46]. 4.…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

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Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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“…Molecular chaperones have been found to be linked to a great extent with Aβ-plaques and neuronal NFTs in astrocytes and oligodendrocytes in the brains of AD patients in comparison to control brain [64] . Molecular chaperones Hsp20, 27, 72 and 90 are linked with Aβ plaques, while Hsp72 and the small Hsp αB-crystallin (20 kDa) are linked with glial but not neuronal NFTs in AD brains.…”

Section: Molecular Chaperone In Admentioning

confidence: 99%

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

Sajjad¹,

Arif²,

Shah³

et al. 2018

pharmaceutical-sciences

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Sajjad, et al.: Pathogenesis of Alzheimer's DiseaseThe pathological emblems of Alzheimer's disease are the accumulation of amyloid-β plaques and neurofibrillary tangles. The alluvium of toxic amyloid-β-protein in the form of aggregates is central to the pathogenesis of Alzheimer's disease. The aggregate formation is due to the structural refitting of α-helical sheet of normal, soluble amyloid-β-protein to the β-sheets, which lead to oligomeric, fibrillar, insoluble and disease causing amyloid-β 42. Mounting data suggests that another factor, the tau protein ripens into highly phosphorylated form by several kinases after Aβ-stimulation leads to tangle formation resulting in neuronal bereavement in hippocampus and entorhinal regions as the disease progresses further. An overview has been presented in this review of the role of tau as an important partner of amyloid-β in the pathogenesis of Alzheimer's disease, both of which could be used as biomarkers for diagnosis and risk assessment with other molecular chaperones, which are associated with Alzheimer's disease. As a part of common pathophysiological mechanism the understanding of amyloid-β and tau toxicities might be helpful for finding molecular targets for the prevention or even cure of Alzheimer's disease.

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March separate, strike together — Role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease

Cited by 98 publications

References 134 publications

Axonal Transport Defects in Alzheimer’s Disease

Axonal Transport Defects in Alzheimer’s Disease

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Pathogenesis of Alzheimer's Disease: Role of Amyloid-beta and Hyperphosphorylated Tau Protein

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