Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments

Grundke‐Iqbal, Inge; Vorbrodt, A; Iqbal, Khalid; Tung, Yunn Chyn; Wang, Gian P.; Wı́sniewski, Henryk M.

doi:10.1016/0169-328x(88)90017-4

Cited by 233 publications

(192 citation statements)

References 28 publications

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“…In Alzheimer disease 75-85% of the MAP tau, including all six isoforms, is altered both in its degree of phosphorylation and its solubility-characteristics [1,3,9,13,16]. In vitro studies have shown that the abnormal hyperphosphorylation of tau renders it biologically inactive [10,11,20].…”

Section: Discussionmentioning

confidence: 99%

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Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

et al. 1995

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In Alzheimer disease (AD) the microtubule associated protein (MAP) tau is hyperphosphorylated at several sites. In the present study, like AD tau, tau in the human neuroblastoma SH-SY5Y was found to be hyperphosphorylated, at Ser-199/202, Thr-231, Ser-396 and Ser-404. However, in contrast to AD, the tau in SY5Y cells was not hyperphosphorylated at Ser-235 and there was only one tau isoform. Quantitative analysis revealed that approximately 80% of the SY5Y-tau was phosphorylated at Ser-199/202. The phosphorylated tau was deposited in perikarya and processes of the cells whereas most of the unphosphorylated (at Ser-199/202) tau was localized in the nucleus. Tau from the cell lysates did not bind to taxol-stabilized microtubules. In contrast, MAPlb and MAP2 from cell lysates bound to stabilized microtubules in vitro and were associated to the microtubule network in situ. Phosphorylation of tau at high levels, its inactivity with microtubules and its accumulation in SY5Y cells provide for the first time a cell model of cytoskeletal changes seen in AD.

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Section: Discussionmentioning

confidence: 99%

“…The protein concentrations were assayed by the modified Lowry method of Bensadoun and Weinstein [12]. In some cases tau was immunoprecipitated from the cell lysates with polyclonal anti-tau antibody, 92e [13] bound to agarose linked protein G (Pierce, Rockford, IL).…”

Section: Cells and Proteinsmentioning

confidence: 99%

Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

et al. 1995

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“…Samples in which overlay with N-tau was substituted with BSA were used to deduct any background binding of Tau-1 to AD P-tau or PHF. A third strip of the membrane was used to detect total tau with a mixture of phosphoindependent polyclonal Abs against tau: 134d (49), 111e (50), and 92e (51) to normalize the data. Two other strips were spotted with N-tau and overlaid with BSA or N-tau to detect unspecific binding and detected with Tau-1 Ab.…”

Section: In Vitro Hyperphosphorylation and Assembly Of Recombinant Humentioning

confidence: 99%

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Alonso¹,

Li²,

Grundke‐Iqbal³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of abnormally hyperphosphorylated tau (P-tau) in the form of tangles of paired helical filaments and͞or straight filaments is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. P-tau is also found unpolymerized in AD. Although the cognitive decline is known to correlate with the degree of neurofibrillary pathology, whether the formation of filaments or the preceding abnormal hyperphosphorylation of tau is the inhibitory entity that leads to neurodegeneration has been elusive. We have previously shown that cytosolic abnormaly hyperphosphorylated tau in AD brain (AD P-tau) sequesters normal tau (N-tau), microtubule-associated protein (MAP) 1, and MAP2, which results in the inhibition of microtubule assembly and disruption of microtubules. Here, we show that polymerization of AD P-tau into filaments inhibits its ability to bind N-tau and as well as the ability to inhibit the assembly of tubulin into microtubules in vitro and in the regenerating microtubule system from cultured cells. Like AD P-tau, the in vitro abnormally hyperphosphorylated recombinant brain N-tau binds N-tau and loses this binding activity on polymerization into filaments. Dissociation of the hyperphosphorylated N-tau filaments by ultrasonication restores its ability to bind N-tau. These findings suggest that the nonfibrillized P-tau is most likely the responsible entity for the disruption of microtubules in neurons in AD. The efforts in finding a therapeutic intervention for tau-induced neurodegeneration need to be directed either to prevent the abnormal hyperphosphorylation of this protein or to neutralize its binding to normal MAPs, rather than to prevent its aggregation into filaments.abnormal hyperphosphorylation of tau ͉ microtubule assembly ͉ microtubule-associated proteins ͉ neurofibrillary degeneration ͉ paired helical filaments A common feature of the dementia disorders that are known as tauopathies [which include Alzheimer's disease (AD) 1 and frontotemporal dementia with Parkinsonism-linked to chromosome 17 ] is the accumulation in the brain neurons of abnormally hyperphosphorylated tau (P-tau), mostly polymerized into tangles of paired helical filaments (PHFs) and/or straight filaments (SF) (1). Besides hyperphosphorylation, tau in PHF͞SF has been shown to be glycated (2), truncated (3), and immunoreactive with an Ab to a stable 4-hydroxy-2-nonenal (HNE)-lysine adduct (4). The number of neurofibrillary tangles is known to correlate directly with the degree of dementia in AD patients (5-7). Also, the recent discovery of the cosegregation of specific mutations in the tau gene with disease in some pedigrees of FTDP-17 has confirmed that the tau pathology can be a primary cause of neurodegeneration and dementia (8-10). Up to 40% of the abnormally hyperphosphorylated tau in AD brain (AD P-tau) is in the cytosol (11-13). Understanding whether this AD P-tau or its polymer, PHF͞SF, initiates the neurodegeneration is critical for developing a rational therapeutic treatment of AD and related tauopathies.The AD...

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“…The phosphorylation-independent tau antibodies 92e and R134d and anti-PP5 antibody were raised in rabbits as described previously (35,44,45). [␥-32 P]ATP was bought from ICN Biomedicals (Costa Mesa, CA).…”

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confidence: 99%

Dephosphorylation of Tau by Protein Phosphatase 5

Liu

Iqbal

Grundke‐Iqbal

et al. 2005

Journal of Biological Chemistry

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Protein phosphatase (PP) 5 is highly expressed in the mammalian brain, but few physiological substrates have yet been identified. Here, we investigated the kinetics of dephosphoryation of phospho-tau by PP5 and found that PP5 had a K m of 8 -13 M toward tau, which is similar to that of PP2A, the major known tau phosphatase. This K m value is within the range of intraneuronal tau concentration in human brain, suggesting that tau could be a physiological substrate of both PP5 and PP2A. PP5 dephosphorylated tau at all 12 Alzheimer's disease (AD)-associated abnormal phosphorylation sites studied, with different efficiency toward each site. Tau protein is a major microtubule-associated protein in neurons. The known biological function of tau protein is to stimulate and stabilize microtubule formation from tubulin subunits. In human brain, there are six tau isoforms generated by alternative mRNA splicing from a single gene (1, 2). Tau is a phosphoprotein that normally contains 2-3 phosphates/molecule, but it is abnormally hyperphosphorylated with a stoichiometry of 9 -10 moles of phosphate per mole of protein in Alzheimer's disease (AD) 1 brain (3, 4). To date, more than 30 phosphorylation sites have been identified in AD hyperphosphorylated tau, some of which are not phosphorylated in normal tau (for review, see Refs. 5 and 6). The abnormally hyperphosphorylated tau is the major component of paired helical filaments (PHFs) (7-10), which form neurofibrillary tangles, a histopathological hallmark brain lesion of AD and several other tauopathies.The hyperphosphorylation of tau appears to be responsible for the loss of its biological function, gain of its toxicity, and aggregation into PHFs (11-16). However, the molecular mechanism by which tau becomes abnormally hyperphosphorylated in AD brain is not yet well understood. Theoretically, the abnormal hyperphosphorylation of tau could be the result of up-regulation of tau kinases or down-regulation of tau phosphatases. Several studies have shown that three major protein phosphatases (PPs), PP1, PP2A, and PP2B, dephosphorylate tau in vitro (17-23). Among these, PP2A appears to be the major phosphatase that regulates tau phosphorylation in the brain (23-28). The activity of PP2A was found to be decreased in AD brain (29 -33). Nevertheless, PP2A does not dephosphorylate all the phosphorylation sites of tau, and down-regulation of PP2A in animal brain could not produce PHFs (26,28). These studies suggest that in addition to PP2A, other phosphatases or factors might also participate in the regulation of tau phosphorylation.PP5 is a 58-KDa phosphoseryl/phosphothreonyl protein phosphatase. It is ubiquitously expressed in all types of mammalian tissue, with a relatively high level in the brain (34,35). PP5 contains a C-terminal catalytic domain structurally related to the PP1/PP2A/PP2B family and an N-terminal regulatory domain consisting of three tetratricopeptide repeats (TPRs) that usually mediate protein-protein interaction. It has been demonstrated that PP5 interacts with mul...

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Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments

Cited by 233 publications

References 28 publications

Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity

Dephosphorylation of Tau by Protein Phosphatase 5

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