Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow, Eva‐Maria

doi:10.1101/cshperspect.a006247

Cited by 652 publications

(619 citation statements)

References 253 publications

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“…16 There were no changes in the levels of glycogen synthase kinase (GSK)-3, protein phosphatase 2a (PP2a), protein kinase A (PKA), and extracellular signal-regulated kinase (ERK) ( Figure S4) or tau acetylation in hippocampal neurons that expressed HDAC2 ( Figure S5). However, we identified a substantial increase in AMPK activity and expression ( Figures 3A and 3B).…”

Section: Hdac2 Enhances Ampk Expression Via Inhibition Of Mir-101bmentioning

confidence: 99%

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Liú

Tang

et al. 2017

Molecular Therapy

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Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Ab overproduction in AD; however, its involvement in tau pathology and other memoryrelated functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4a (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.

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Section: Hdac2 Enhances Ampk Expression Via Inhibition Of Mir-101bmentioning

confidence: 99%

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Liú

Tang

et al. 2017

Molecular Therapy

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“…We found no difference in basal synaptic transmission between WT and Tau DN/DN mice (Figure 5a). However, LTP, a long-lasting form of synaptic plasticity that is associated with learning and memory, was reduced in Tau DN/DN mice as compared with WT littermate control animals (F (1,14) = 5.390, P = 0.0359) (Figure 5b). Thus, the Tau DN/DN mutation compromises LTP in older mice.…”

Section: Generation Of Tau Dn Micementioning

confidence: 99%

“…Recent data suggest that a fraction of Tau protein is localized extracellularly. [1][2][3][4] However, the biological function of extracellular tau is unknown.…”

Section: Introductionmentioning

confidence: 99%

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

et al. 2017

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TAU mutations are genetically linked to fronto-temporal dementia (FTD) and hyper-phosphorylated aggregates of Tau form neurofibrillary tangles (NFTs) that constitute a pathological hallmark of Alzheimer disease (AD) and FTD. These observations indicate that Tau has a pivotal role in the pathogenesis of neurodegenerative disorders. Tau is cleaved by caspases at Aspartate 421 , to form a Tau metabolite known as δTau; δTau is increased in AD, due to the hyper-activation of caspases in AD brains. δTau is considered a critical toxic moiety underlying neurodegeneration, which initiates and facilitates NFT formation. As Tau is a therapeutic target in neurodegeneration, it is important to rigorously determine whether δTau is a toxic Tau species that should be pharmacologically attacked. To directly address these questions, we have generated a knock-in (KI) mouse called Tau DN -that expresses a Tau mutant that cannot be cleaved by caspases. Tau DN mice present short-term memory deficits and synaptic plasticity defects. Moreover, mice carrying two mutant Tau alleles show increased total insoluble hyper-phosphorylated Tau in the forebrain. These data are in contrast with the concept that δTau is a critical toxic moiety underlying neurodegeneration, and suggest that cleavage of Tau by caspases represents a negative feedback mechanism aimed to eliminate toxic Tau species. Alternatively, it is possible that either a reduction or an increase in δTau leads to synaptic dysfunction, memory impairments and Tau pathology. Both possibilities will have to be considered when targeting caspase cleavage of Tau in AD therapy.

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“…Some of the cellular structures and proteins for which interaction of the respective domains has been suggested are designated by the arrows shown below. This scheme summarizes informations from several excellent reviews, from which more detailed descriptions of the different modifications and their effect on tau in addition to those mentioned in the text can be obtained: [8,9,10,11,12]. (B) Different oligomerization states of tau are shown.…”

Section: Tau Hyperphosphorylation and Its Relation To Admentioning

confidence: 99%

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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Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Cited by 652 publications

References 253 publications

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Abolishing Tau cleavage by caspases at Aspartate421 causes memory/synaptic plasticity deficits and pre-pathological Tau alterations

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

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