Tau: From research to clinical development

Holtzman, David M.; Carrillo, María C.; Hendrix, James A.; Bain, Lisa J.; Catafau, Ana M.; Gault, Laura M.; Goedert, Michel; Mandelkow, Eckhard; Mandelkow, Eva‐Maria; Miller, David S.; Ostrowitzki, Susanne; Polydoro, Manuela; Smith, Sean M.; Wittmann, Marion; Hutton, Michael

doi:10.1016/j.jalz.2016.03.018

Cited by 128 publications

(111 citation statements)

References 63 publications

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“…3 In this study, we determined that HDAC2 overexpression mainly affects tau phosphorylation. The screening of known tau kinases and phosphatases identified AMPK as a prominent effector.…”

Section: Discussionmentioning

confidence: 98%

“…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. 4 Thus, the alleviation of tauopathy via target-specific and disease-modifying treatments is a promising therapeutic strategy for AD.…”

Section: Introductionmentioning

confidence: 99%

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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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“…3 In this study, we determined that HDAC2 overexpression mainly affects tau phosphorylation. The screening of known tau kinases and phosphatases identified AMPK as a prominent effector.…”

Section: Discussionmentioning

confidence: 98%

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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“…Anti-tau therapeutic approaches have included attempts to restore the normal function of the tau protein by inhibition of tau phosphorylation (Del Ser et al , 2013) and tau aggregation (Anand et al , 2014). Other therapeutic strategies have focused on reducing accumulation or spread of tau aggregates (Holtzman et al , 2016). Recently, infusion of an anti-tau antibody was shown to block propagation of tau pathology and improve cognition in a mouse model of Alzheimer’s disease (Yanamandra et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

Pontecorvo¹,

Devous²,

Navitsky³

et al. 2017

Brain

260

274

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“…We wondered whether different tau mutations may also impact tau clearance differently. Our groups and others have shown the degradation of wild‐type forms of tau through the ubiquitin/proteasome system and through autophagy and failure to degrade some mutant forms of tau through these pathways (Lee et al ., 2013; Holtzman et al ., 2016; Wang & Mandelkow, 2016). However, the degradation pathways of different physiological tau isoforms and the effect of disease‐related point mutations and posttranslational modifications on tau degradation remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Tau: From research to clinical development

Cited by 128 publications

References 63 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

Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition

Interplay of pathogenic forms of human tau with different autophagic pathways

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