Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival

Shimura, Hideki; Miura-Shimura, Yuko; Kosik, Kenneth S.

doi:10.1074/jbc.m400351200

Cited by 179 publications

(162 citation statements)

References 40 publications

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“…Several neurodegenerative diseases appear to have an impaired stress response, further compromising both neuronal function and survival (Bruening et al, 1999;Kobayashi et al, 2000;Auluck et al, 2002;Batulan et al, 2003;Shimura et al, 2004). It is therefore important to understand the intracellular signaling mechanisms affected by the accumulation of toxic proteins in the context of the cellular stress response.…”

Section: Discussionmentioning

confidence: 99%

Intraneuronal β-Amyloid Expression Downregulates the Akt Survival Pathway and Blunts the Stress Response

Magrané¹,

Rosen²,

Smith³

et al. 2005

J. Neurosci.

109

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Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of ␤-amyloid (A␤) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal A␤ on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of A␤42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal A␤42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3␤, and apoptosis. Downregulation of Akt also paralleled intracellular A␤ accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of A␤ through a mechanism involving the induction of heat shock proteins (Hsps). We used a small-interfering RNA approach to explore the possibility of a link between Akt activity and Hsp70 expression and concluded that neuroprotection by Akt could be mediated through downstream induction of Hsp70 expression. These results suggest that the early dysfunction associated with intraneuronal A␤ accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response.

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Section: Discussionmentioning

confidence: 99%

Intraneuronal β-Amyloid Expression Downregulates the Akt Survival Pathway and Blunts the Stress Response

Magrané¹,

Rosen²,

Smith³

et al. 2005

J. Neurosci.

109

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“…It could act as a spacer, or interact with other proteinsfor example, signaling molecules such as kinases, phosphatases, heat shock proteins (HSPs) and other cytoskeletal elements. [22][23][24][25] Because MAPs and microtubule motors both bind to the surface of microtubules, they can potentially interfere with each other. Thus, the overexpression of tau can retard motor-dependent transport, particularly in the anterograde direction.…”

Section: Figmentioning

confidence: 99%

“…170 Note, however, that the beneficial effect on tau clearance by stimulating autophagy might be counteracted by increased A␤ production in the autophagosomal system, as has been proposed by Rubinsztein et al 171,172 The chaperones HSP27 and HSP90 are involved in phosphorylation-dependent proteasomal degradation of tau. 24,173 HSP90-interacting proteins are degraded by the proteasome upon pharmacological inhibition of HSP90. Phosphorylation of the flanking regions enhanced the proteasomal degradation of tau in transfected cell lines that were treated with HSP90 inhibitors.…”

Section: Tau Clearancementioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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“…Indeed, many examples of antibody-profections already exist. 50,[62][63][64][65][74][75][76]78,80,[82][83][84][85][86][87][88][89][90] It is unclear why this approach is not more widely employed since there are numerous promising applications. One of the obstacles previously mentioned is the potential loss of protein activity upon association with the transfection reagent.…”

confidence: 99%