Distribution, Levels, and Activity of Glycogen Synthase Kinase-3 in the Alzheimer Disease Brain

Pei, Jin-Jing; Tanaka, Toshihisa; Tung, Yunn Chyn; Braak, Eva; Iqbal, Khalid; Grundke‐Iqbal, Inge

doi:10.1097/00005072-199701000-00007

Cited by 328 publications

(214 citation statements)

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“…125 Active GSK-3 was detected in pretangle neurons and NFTs in AD brains, and coexpression of the GSK-3 homolog shaggy with tau led to tau hyperphosphorylation, filamentous tau aggregation, and neurotoxicity in Drosophila fruit fly. 126,127 In line with these findings, GSK-3␤ overexpressing transgenic mice showed increased tau phosphorylation and deficits in spatial memory. 128,129 Tau phosphorylation by GSK-3 can be enhanced by A␤ -treatment, which thus provides a possible link between tau and A␤ pathology.…”

Section: Antiphosphorylation Strategiessupporting

confidence: 54%

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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Section: Antiphosphorylation Strategiessupporting

confidence: 54%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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“…21). In the few studies that have assessed GSK3␤ in AD, increased levels of GSK3␤ were found in AD, compared with non-diseased, human brain; immunohistochemical measurements found GSK3␤ associated with neurofibrillary tangles in AD brain (82)(83)(84)(85)(86); and active GSK3␤ was found to be accumulated in pretangle neurons (86). Furthermore, the AD-associated A␤ peptide is known to activate GSK3␤ (22), and the GSK3␤ inhibitor lithium provides protection from A␤ toxicity (87,88).…”

Section: Discussionmentioning

confidence: 99%

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Lee

Sarno

Jope

2002

Journal of Biological Chemistry

254

240

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Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca 2؉ -ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3␤ (GSK3␤). Activation of GSK3␤ was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3␤ by expression of dominantnegative GSK3␤ or by the GSK3␤ inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3␤ by inducing dephosphorylation of phospho-Ser-9 of GSK3␤, a phosphorylation that normally maintains GSK3␤ inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3␤ with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3␤ through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.

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“…Protein Kinase Activity Assay-The GSK-3 activity in rat hippocampal extracts was measured using phospho-GS peptide 2 as described previously (32)(33)(34). Briefly, tissue extract, 7.5 g of protein was incubated for 30 min at 30°C with 20 M peptide substrate and 200 M [␥-32 P]ATP (1500 cpm/pmol of ATP) in 30 mM Tris, pH 7.4, 10 mM MgCl 2 , 10 mM NaF, 1 mM Na 3 VO 4 , 2 mM EGTA, and 10 mM ␤-mercaptoethanol in a total volume of 25 l. The reaction was stopped by addition of 25 l of 300 mM O-phosphoric acid.…”

Section: Methodsmentioning

confidence: 99%

“…These tissue blocks were further fixed in the same Zamboni's solution for another 12 h at 4°C, paraffin-embedded, and cut into 5-m-thick sections. The immunocytochemical staining was performed as described previously (32,41). Briefly, the tissue sections were first treated with 100 mM NaOH at room temperature for 30 min, followed by incubation at 4°C for 48 h with one of the following primary antibodies: PS214 (1:500), Tau-1 (1:30,000), or PHF-1 (1:500).…”

Section: Methodsmentioning

confidence: 99%

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

Liu

Zhang

et al. 2004

Journal of Biological Chemistry

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173

116

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Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R p -adenosine 3 ,5 -cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

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Distribution, Levels, and Activity of Glycogen Synthase Kinase-3 in the Alzheimer Disease Brain

Cited by 328 publications

References 0 publications

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Tau-Based Treatment Strategies in Neurodegenerative Diseases

Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation

Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain

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