Phosphorylated Tau Protein Is Integrated into Paired Helical Filaments in Alzheimer's Disease1

Ihara, Yasuo; Nukina, Nobuyuki; Miura, Reiko; Ogawara, Midori

doi:10.1093/oxfordjournals.jbchem.a135662

Cited by 477 publications

(212 citation statements)

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“…T protein is a poor substrate for cAMP-kinase in vitro, but is phosphorylated in mode II (mobility on SDS/polyacrylamide gels does not change) by protein kinase C [66]. Interestingly, the mobility shift induced by mode I phosphorylation resembles that which has been observed in r protein purified from the paired helical filaments of degenerative neurons in Alzheimer's disease [67,68]. Like MAP-2, r protein is also known to promote microtubule protein polymerization, and mode I phosphorylation ofT protein inhibits this stimulation of microtubule formation [69].…”

Section: Species Tissue and Subcellular Distributionmentioning

confidence: 89%

Calcium/Calmodulin-Dependent Protein Kinase II

Colbran

Soderling

1990

Current Topics in Cellular Regulation

173

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Section: Species Tissue and Subcellular Distributionmentioning

confidence: 89%

Calcium/Calmodulin-Dependent Protein Kinase II

Colbran

Soderling

1990

Current Topics in Cellular Regulation

173

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“…PHF-tau accumulate in the brain of Alzheimer's disease patients and the main component is tau [23][24][25]. It has been reported that PHF-tau is highly phosphorylated in the tau 1 portion [26] and carboxy-terminal portion [27].…”

Section: Discussionmentioning

confidence: 99%

A novel tau‐tubulin kinase from bovine brain

et al. 1995

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During purification oftau protein kinase I and II from the bovine brain extract, a new tau protein kinase was detected and purified with phosphocellulose, gel filtration, S-Sepharose and AF-Heparin column chromatography. The molecular mass of the enzyme was determined to be 32 kDa by gel filtration and activity staining on SDS-PAGE. The enzyme is a Ser/Thr protein kinase phosphorylating tau, l~-tubulin, MAP2 and ~-casein. Employing many synthetic peptides, the recognition site of this enzyme appears to be -SR-. The enzyme requires no second messenger and is inhibited with high concentration of heparin, but not by inhibitors of CKI. These results indicate that this enzyme, tau-tubulin kinase is novel and distinct from TPKI, II and CKI, II.

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“…Tel: 210-567-0713; Fax: 210-567-4410; E-mail: oddo@uthscsa.edu. 3 The abbreviations used are: AD, Alzheimer disease; A␤, amyloid-␤; APP, amyloid precursor protein; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; PRAS40, proline-rich Akt substrate 40; NonTg, non-transgenic; CM, conditioned medium; Bis-Tris, 2-(bis(2-hydroxyethyl)-amino)-2-(hydroxymethyl)propane-1,3-diol. …”

mentioning

confidence: 99%

“…Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2)(3)(4).…”

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confidence: 99%

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Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

154

132

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Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing A␤ accumulation. Similarly, intrahippocampal injections of an anti-A␤ antibody reduced A␤ levels and normalized mTOR activity, indicating that high A␤ levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted A␤ is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the A␤-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the A␤-induced mTOR hyperactivity. Taken together, our data show that A␤ accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which A␤ exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2-4). Plaques are extracellular inclusions mainly formed of a small peptide called amyloid-␤ (A␤) (5, 6). Clinically, AD is characterized by profound memory loss and cognitive dysfunction (7). Growing evidence is converging on soluble A␤ as a mediator of early cognitive decline in AD (8, 9). Although the molecular mechanisms underlying A␤-induced cognitive decline remain elusive, soluble A␤ oligomers have been shown to alter signal transduction pathways that are key for learning and memory, suggesting that alterations in such pathways may underlie the onset of cognitive decline in AD (10).The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (11). mTORC1 controls protein homeostasis; its activity is inhibited by rapamycin, and it contains mTOR, raptor, proline-rich Akt substrate 40 kDa (PRAS40), and mLT8. mTORC2, which is insensitive to rapamycin, controls cellular shape by modulating actin function and contains mTOR, rictor, mLST8, and hSIN (11, 12). In mTORC1, raptor binds to mTOR substrates and is necessary for mTOR activity (13). PRAS40 is another mTOR regulatory protein, which inhibits mTOR...

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Phosphorylated Tau Protein Is Integrated into Paired Helical Filaments in Alzheimer's Disease1

Cited by 477 publications

References 0 publications

Calcium/Calmodulin-Dependent Protein Kinase II

Calcium/Calmodulin-Dependent Protein Kinase II

A novel tau‐tubulin kinase from bovine brain

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

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