Hyperphosphorylation determines both the spread and the morphology of tau pathology

Hu, Wen; Zhang, Xinhua; Tung, Yunn Chyn; Xie, Shutao; Liu, Fei; Iqbal, Khalid

doi:10.1016/j.jalz.2016.01.014

Cited by 106 publications

(103 citation statements)

References 49 publications

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“…The assembly of those structures could be facilitated by the presence of other compounds or by differences in the level of tau phosphorylation. Indeed phospho-tau dephosphorylation by protein phosphatase 2A could switch the formation of fibrillary polymers to argylophilic gain-like morphology (Hu et al, 2016). Curiously, injection in mouse brain of brain extracts from patients with tauopathies showing different tau structures could reproduce “ in vivo ” the appearance, in mouse, of those structures (Clavaguera et al, 2013; Sanders et al, 2014).…”

Section: Tau Quaternary Structurementioning

confidence: 99%

Tau Structures

Ávila

Jiménez

Sayas

et al. 2016

Front. Aging Neurosci.

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Tau is a microtubule-associated protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. In this review, we focus on the primary, secondary, tertiary, and quaternary tau structures. We describe the structure of tau from its specific residues until its conformation in dimers, oligomers, and larger polymers in physiological and pathological situations.

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Section: Tau Quaternary Structurementioning

confidence: 99%

Tau Structures

Ávila

Jiménez

Sayas

et al. 2016

Front. Aging Neurosci.

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“…This finding, which formed the basis of tau spread studies [33–36], led us to test the removal of pathological tau by passive immunization using antibodies to N-terminal domains of tau.…”

Section: Introductionmentioning

confidence: 99%

“…The abnormally hyperphosphorylated/oligomeric tau released in the extracellular space from the affected neurons is suspected to serve as the seed for the spread of tau pathology by the ingesting cells [33, 36, 39, 40]. Tau immunotherapy may clear extracellular tau that is involved in the spreading of tau pathology [23, 41].…”

Section: Introductionmentioning

confidence: 99%

Tau passive immunization inhibits not only tau but also Aβ pathology

et al. 2017

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BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6–18 and 77E9 against tau 184–195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6–18 as a disease-modifying approach to AD and related tauopathies.

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“…1 Neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau proteins 2 are the major neuropathological hallmarks of AD and correlate with cognitive decline. 3 This tau-induced pathology may promote dendritic abnormalities, synaptic dysfunction, and memory impairment.…”

Section: Introductionmentioning

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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Hyperphosphorylation determines both the spread and the morphology of tau pathology

Cited by 106 publications

References 49 publications

Tau Structures

Tau Structures

Tau passive immunization inhibits not only tau but also Aβ pathology

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

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