GSK3: A possible link between beta amyloid peptide and tau protein

Hernández, Félix; Barreda, Elena Gómez de; Fuster-Matanzo, Almudena; Lucas, José J.; Ávila, Jesús

doi:10.1016/j.expneurol.2009.09.011

Cited by 264 publications

(175 citation statements)

References 63 publications

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“…calcium-calmodulin kinase II (CaMKII) with KN-93, of the nonreceptor tyrosine kinases, fyn and src, with PP2, or of the cyclic AMP-dependent protein kinase A (PKA) with KT5720 blocked BrdU uptake, and thus CCR, in WT neurons. CCR was also blocked by the mTOR inhibitor, rapamycin, as reported earlier (Bhaskar et al, 2009), but not by Ag1024, an inhibitor of IGF-1 and insulin receptor kinase, which act upstream of mTOR (Zoncu et al, 2011), nor by glycogen synthase kinase3b (GSK3b) inhibitor II, which potently blocks GSK3b, a major tau kinase that can be activated by Ab (Hernández et al, 2010).…”

Section: Neuronal Ccr Requires Tausupporting

confidence: 58%

“…5B). Therefore, despite the widely recognized importance of GSK3b-catalyzed phosphorylation of tau in AD (Hernández et al, 2010), GSK3b does not appear to be involved in neuronal CCR. Secondly, the present study establishes that the CCR-mediated pathway of neurodegeneration in AD results from a direct functional link between Ab and tau, the principal building blocks of plaques and tangles.…”

Section: Discussionmentioning

confidence: 95%

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Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease

Seward

Swanson

Norambuena

et al. 2013

Journal of Cell Science

154

146

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SummaryNormally post-mitotic neurons that aberrantly re-enter the cell cycle without dividing account for a substantial fraction of the neurons that die in Alzheimer's disease (AD). We now report that this ectopic cell cycle re-entry (CCR) requires soluble amyloid-b (Ab) and tau, the respective building blocks of the insoluble plaques and tangles that accumulate in AD brain. Exposure of cultured wild type (WT) neurons to Ab oligomers caused CCR and activation of the non-receptor tyrosine kinase, fyn, the cAMP-regulated protein kinase A and calcium-calmodulin kinase II, which respectively phosphorylated tau on Y18, S409 and S416. In tau knockout (KO) neurons, Ab oligomers activated all three kinases, but failed to induce CCR. Expression of WT, but not Y18F, S409A or S416A tau restored CCR in tau KO neurons. Tau-dependent CCR was also observed in vivo in an AD mouse model. CCR, a seminal step in AD pathogenesis, therefore requires signaling from Ab through tau independently of their incorporation into plaques and tangles.

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Section: Neuronal Ccr Requires Tausupporting

confidence: 58%

Section: Discussionmentioning

confidence: 95%

Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease

Seward

Swanson

Norambuena

et al. 2013

Journal of Cell Science

154

146

View full text Add to dashboard Cite

show abstract

“…However, neither roscovitine nor roscovitine S-isomer, two pan-cyclin-dependent kinase inhibitors included in our library, were effective against the CLuc-FGF14⅐CD4-Nav1.6-NLuc channel complex (79 Ϯ 23% S.D., n ϭ 4, and 98 Ϯ 23% S.D., n ϭ 2, respectively), providing further evidence for a GSK3-specific effect on our target. Identification of GSK3 inhibitors as hits was of particular significance due to the documented role of GSK3 in regulating neuronal polarity (30), synaptic plasticity (31), and ion channels (20) and considering its relevance as a therapeutic target against brain disorders (32,33).…”

Section: Kinase Inhibitor Screening Of the Fgf14⅐nav Channelmentioning

confidence: 99%

The Fibroblast Growth Factor 14·Voltage-gated Sodium Channel Complex Is a New Target of Glycogen Synthase Kinase 3 (GSK3)

Shavkunov

Wildburger²,

Nenov³

et al. 2013

Journal of Biological Chemistry

160

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“…The prevalence and chronology of these phosphorylation events have been rigorously correlated with AD tangle pathology (5,6). GSK3␤ is a primary kinase for several key sites that are associated with Tau pathology, and it can lead to Tau hyperphosphorylation (37). Here, we have created a hyperphosphorylating environment for Tau by overexpressing a constitutively active form of GSK3␤.…”

Section: A Hyperphosphorylating Environment Blocks Folding Of Tau Butmentioning

confidence: 99%

Hsc70 Rapidly Engages Tau after Microtubule Destabilization

Jinwal

O’Leary

Borysov

et al. 2010

Journal of Biological Chemistry

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The microtubule-associated protein Tau plays a crucial role in regulating the dynamic stability of microtubules during neuronal development and synaptic transmission. In a group of neurodegenerative diseases, such as Alzheimer disease and other tauopathies, conformational changes in Tau are associated with the initial stages of disease pathology. Folding of Tau into the MC1 conformation, where the amino acids at residues 7-9 interact with residues 312-342, is one of the earliest pathological alterations of Tau in Alzheimer disease. The mechanism of this conformational change in Tau and the subsequent effect on function and association to microtubules is largely unknown. Recent work by our group and others suggests that members of the Hsp70 family play a significant role in Tau regulation. Our new findings suggest that heat shock cognate (Hsc) 70 facilitates Tau-mediated microtubule polymerization. The association of Hsc70 with Tau was rapidly enhanced following treatment with microtubule-destabilizing agents. The fate of Tau released from the microtubule was found to be dependent on ATPase activity of Hsc70. Microtubule destabilization also rapidly increased the MC1 folded conformation of Tau. An in vitro assay suggests that Hsc70 facilitates formation of MC1 Tau. However, in a hyperphosphorylating environment, the formation of MC1 was abrogated, but Hsc70 binding to Tau was enhanced. Thus, under normal circumstances, MC1 formation may be a protective conformation facilitated by Hsc70. However, in a diseased environment, Hsc70 may preserve Tau in a more unstructured state, perhaps facilitating its pathogenicity.

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GSK3: A possible link between beta amyloid peptide and tau protein

Cited by 264 publications

References 63 publications

Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease

Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease

The Fibroblast Growth Factor 14·Voltage-gated Sodium Channel Complex Is a New Target of Glycogen Synthase Kinase 3 (GSK3)

Hsc70 Rapidly Engages Tau after Microtubule Destabilization

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