Synergistic Control Mechanism for Abnormal Site Phosphorylation of Alzheimer′s Diseased Brain Tau by Kinase FA/GSK-3α

Yang, Shiaw Der; Yu, Jau‐Song; Liu, Wan Kyng; Yen, Shu Hui

doi:10.1006/bbrc.1993.2493

Cited by 12 publications

(6 citation statements)

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“…Ser262 and Thr231, the phosphorylated epitopes of which are recognized by pSer262 and AT180, respectively, 26 are important sites for p‐NFT formation 2 . In particular, AT180‐positive NFT density was positively correlated with H8‐beta and zeta‐positive NFT in the present study and Thr231 is presumed to be one of the initial phosphorylation sites of tau 2,3 in addition to Ser199 and Ser202 27–32 in NFT. Therefore, phosphorylation of Thr231 is believed to be involved in the development of p‐NFT 2 .…”

Section: Discussionsupporting

confidence: 57%

14‐3‐3 protein beta isoform is associated with 3‐repeat tau neurofibrillary tangles in Alzheimer's disease

Sugimori

Kobayashi

Kitamura

et al. 2007

Psychiatry Clin Neurosci

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Abstract14-3-3 proteins play roles in phosphorylation of tau proteins in neurofibrillary tangles (NFT) in Alzheimer's disease (AD).Tau is phosphorylated at serine (pSer) and threonine (pThr) in NFT, and NFT morphology varies according to phosphorylated sites and tau isoform. The roles of 14-3-3 proteins in NFT morphology remain unknown. This study was performed to examine the relationships between 14 and 3-3 proteins and tau phosphorylation of NFT. NFT were labeled with Gallyas impregnation, tau and 14-3-3 immunohistochemistry in paraffin-embedded hippocampal sections from seven AD and three control brains. Anti-tau antisera included monoclonal antisera that recognize pSer262 (pSer262), pSer422 (pSer422), pSer202/pThr205 (AT8), Thr231 (AT180), threerepeat (RD3) and four-repeat (RD4) tau isoform. Anti-14-3-3 protein isoform antisera included polyclonal antisera to beta, gamma, zeta, epsilon, tau, mu and sigma isoforms and monoclonal antiserum to beta antiserum (H8-beta). NFT density was obtained by counting labeled NFT in cornu ammonis (CA) 1-CA4, subiculum and entorhinal cortex. H8-beta and zeta isoforms were strongly expressed in NFT. Regional densities of NFT positive for pSer262, AT8, AT180, and Gallyas impregnation were similar to RD3-positive NFT density with high densities in CA1 and entorhinal cortex. NFT positive for pSer422 showed a similar regional distribution to RD4-positive NFT with high NFT density in CA2-CA4. H8-beta-positive NFT showed a similar regional distribution to RD3-positive NFT. In contrast, zeta isoform-positive NFT showed no specific distribution. In conclusion, H8-beta isoform is associated with development of 3-repeats NFT but a role of 14-3-3 zeta isoform in NFT could not be specified.

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Section: Discussionsupporting

confidence: 57%

14‐3‐3 protein beta isoform is associated with 3‐repeat tau neurofibrillary tangles in Alzheimer's disease

Sugimori

Kobayashi

Kitamura

et al. 2007

Psychiatry Clin Neurosci

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“…In our study, AT180-positive NFT density was especially predominant in the CA, entorhinal and cingulate cortex, as it was when all regions were included. AD-associated abnormal phosphorylation starts at Ser199 and Ser202 in the neuropil threads, but some studies [26][27][28] reported that the earliest abnormal phosphorylation was shown to occur around Thr231 in AD and the extent of phosphorylation was greater than at other sites. AT180 as well as AT8 labeled few neuritic profiles in the neuropil and the quantitative results of our study indicate that Thr231 is an initial phosphorylation site of neuronal cytoplasmic NFT associated with the AD-related phosphorylation process.…”

Section: Discussionmentioning

confidence: 99%

Regional Analysis of Differently Phosphorylated Tau Proteins in Brains from Patients with Alzheimer’s Disease

Nakano

Kobayashi

Sugimori

et al. 2004

Dement Geriatr Cogn Disord

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Neurofibrillary tangles (NFT) in Alzheimer’s disease (AD) are composed of abnormally phosphorylated tau proteins. Many phosphorylation sites have been reported in the AD brain, and NFT distribution was now roughly classified into 3 stages by Braak stage; this classification is based on pathological studies using the specific silver impregnation technique. The aim of our study was to examine the regional distribution of differently phosphorylated tau proteins with 5 site-specific monoclonal antibodies against the tau proteins, AT8, AT180, HT7, Tau2 and Tau5. We then compared our findings with those obtained from silver-stained NFT in an attempt to clarify the relationship between abnormal phosphorylation sites of the tau protein and NFT development. AT180 and AT8 labeled the highest and Tau2 the lowest density of NFT in any regions, while Tau5 and HT7 showed inconsistent distribution. In the limbic cortex, cornu ammonis, entorhinal cortex and cingulate cortex, silver-stained NFT density significantly correlated with density of NFT labeled with the 5 anti-tau antibodies, but cerebral isocortices showed heterogenous patterns of tau-positive NFT. Quantification of tau-positive regional NFT density showed that the AD-associated phosphorylation process progresses from the C-terminal to the N-terminal of the amino acid sequence, and correlation of Gallyas-stained NFT density with tau-labeled NFT density was more significant in the limbic cortices than the cerebral isocortices, which implies that stereotypical phosphorylation occurs in the limbic structures.

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“…The study of glycogen synthase phosphorylation indicates that most GSK-3b substrates must first be phosphorylated at Ser or Thr residues for maximal phosphorylation to occur; moreover, priming at Ser235 is essential for GSK-3a-mediated phosphorylation of tau peptides at Thr231 [Yang et al, 1993b]. This finding prompted the intensive study of GSK-3b interactions with other tau kinases.…”

Section: Gsk-3b Phosphorylates Tau In Vitromentioning

confidence: 99%

Role of GSK‐3β in Alzheimer's disease pathology

Planel

Sun

Takashima

2002

Drug Development Research

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Glycogen synthase kinase 3b (GSK-3b) is an important regulatory kinase involved in multiple processes such as metabolic control, embryonic development, cell death, and oncogenesis. It has been found to interact with many molecules associated with Alzheimer's disease (AD) such as the microtubule-associated protein tau, presenilin 1, the amyloid-b peptide, the amyloid precursor protein, and acetylcholine. Furthermore, GSK-3b might be involved in brain aging and longevity. As GSK-3b is associated with so many components of AD pathology, we review the current data on the role of this kinase in tau hyperphosphorylation, then look at its association with AD-related molecules and pathways, and finally discuss its involvement in cell death and aging. We attempt to integrate all these data to arrive at the proposition that GSK-3b is a pivotal molecule in the evolution of AD and that developing drugs directed at this kinase might prove to be beneficial in the treatment of this devastating disease. Drug Dev.

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Synergistic Control Mechanism for Abnormal Site Phosphorylation of Alzheimer′s Diseased Brain Tau by Kinase FA/GSK-3α

Cited by 12 publications

References 0 publications

14‐3‐3 protein beta isoform is associated with 3‐repeat tau neurofibrillary tangles in Alzheimer's disease

14‐3‐3 protein beta isoform is associated with 3‐repeat tau neurofibrillary tangles in Alzheimer's disease

Regional Analysis of Differently Phosphorylated Tau Proteins in Brains from Patients with Alzheimer’s Disease

Role of GSK‐3β in Alzheimer's disease pathology

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