Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration (original) (raw)
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Proceedings of The National Academy of Sciences, 1986
A monoclonal antibody to the microtubuleassociated protein X (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody also labeled isolated PHF that had been repeatedly washed with NaDodSO4. Dephosphorylation of the tissue sections with alkaline phosphatase prior to immunolabeling dramatically increased the number of tangles and plaques recognized by the antibody. The plaque core amyloid was not stained in either dephosphorylated or nondephosphorylated tissue sections. On immunoblots PHF polypeptides were labeled readily only when dephosphorylated. In contrast, a commercially available monoclonal antibody to a phosphorylated epitope of neurordaments that labeled the tangles and the plaque neurites in tissue did not label any PHF polypeptides on immunoblots. The PHF polypeptides, labeled with the monoclonal antibody to 7, electrophoresed with those polypeptides recognized by antibodies to isolated P1F. The antibody to 7-labeled microtubules from normal human brains assembled in vitro but identically treated Alzheimer brain preparations had to be dephosphorylated to be completely recognized by this antibody. These findings suggest that 7 in Alzheimer brain is an abnormally phosphorylated protein component of PH1.
FEBS Letters, 1996
The microtubule-associated protein tau in human brain consists of six molecular isoforms derived from a single gene by alternative mRNA-splicing and further modified by posttranslational processing. In the present study, the distribution of tau isoforms in grey and white matter of human temporal cortex was investigated by two-dimensional gelelectrophoresis. More than 80 isoforms were detected. The pattern of isoforms obtained after treatment with alkaline phosphatase was still more complex than those of recombinant tau, indicating that posttranslational modifications other than phosphorylation contribute to the molecular heterogeneity of tau. The tau isoform D according to Goedert [I] containing four tubulin-binding regions shown to promote tubulin polymerisation most efficiently was present in higher amounts in white as compared to grey matter. The pattern of isoform distribution was not significantly altered in Alzheimer's disease. It is concluded that molecular isoforms that differ in their tubulin-binding characteristics are differentially distributed in subceliular neuronal compartments and/or neuronal types.
Acta Neuropathol, 1999
Microtubule-associated protein tau forms neurofibrillary lesions in Alzheimer's disease and several other neurodegenerative disorders, such as Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy and motor neuron disease with neurofibrillary tangles. In this study we have compared the characteristics of tau pathology in these diseases using immunohistochemistry and phosphorylation-dependent and phosphorylation-independent antitau antibodies. The pattern of staining for heparan sulphate and α-synuclein was also investigated. We show that in all of these diseases tau deposits were stained by all antitau antibodies used, with the exception of argyrophilic grains which do not stain with antibody 12E8, confirming our previous findings. Heparan sulphate staining was present to a variable extent in all of these diseases, with the exception of subacute sclerosing panencephalitis, in which no staining was observed. Heparan sulphate staining coexisted with tau staining. In some cases it was more extensive than the tau staining. α-Synuclein staining was present in presynaptic terminals with the exception of one case of Alzheimer's disease, in which α-synuclein-positive Lewy bodies were observed in the hippocampal formation. These findings indicate that tau deposits are antigenically similar in several neurodegenerative diseases and that tau staining is often associated with heparan sulphate staining, supporting the concept that heparan sulphate may be involved in the assembly of tau protein into filaments.
Acta Neuropathologica, 1999
Microtubule-associated protein tau forms neurofibrillary lesions in Alzheimer's disease and several other neurodegenerative disorders, such as Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy and motor neuron disease with neurofibrillary tangles. In this study we have compared the characteristics of tau pathology in these diseases using immunohistochemistry and phosphorylation-dependent and phosphorylation-independent antitau antibodies. The pattern of staining for heparan sulphate and α-synuclein was also investigated. We show that in all of these diseases tau deposits were stained by all antitau antibodies used, with the exception of argyrophilic grains which do not stain with antibody 12E8, confirming our previous findings. Heparan sulphate staining was present to a variable extent in all of these diseases, with the exception of subacute sclerosing panencephalitis, in which no staining was observed. Heparan sulphate staining coexisted with tau staining. In some cases it was more extensive than the tau staining. α-Synuclein staining was present in presynaptic terminals with the exception of one case of Alzheimer's disease, in which α-synuclein-positive Lewy bodies were observed in the hippocampal formation. These findings indicate that tau deposits are antigenically similar in several neurodegenerative diseases and that tau staining is often associated with heparan sulphate staining, supporting the concept that heparan sulphate may be involved in the assembly of tau protein into filaments.
Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases
FEBS Letters, 1997
Tau proteins aggregate into different neuronal inclusions in several neurodegenerative disorders. In Alzheimer's disease (AD), hyperphosphorylated Tau from paired helical filaments (PHF) of neurofibrillary tangles, named PHF‐Tau, have an electrophoretic profile with four main bands (Tau 55, 64, 69, 74 kDa). In Pick's disease, phosphorylated Tau from Pick bodies are made of two major components (Tau 55, 64 kDa) and a minor 69 kDa. Here we show, using specific antibodies against translated exon 2, 3 or 10 of Tau isoforms, that the set of Tau isoforms engaged in the most insoluble part of PHF in AD is made of Tau isoforms with exon 10 while they are lacking in phosphorylated Tau from Pick's disease. Our results suggest that specific sets of Tau isoforms distinguish between typical neuronal inclusions.
Acta Neuropathologica, 1999
Microtubule-associated protein tau forms neurofibrillary lesions in Alzheimer's disease and several other neurodegenerative disorders, such as Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy and motor neuron disease with neurofibrillary tangles. In this study we have compared the characteristics of tau pathology in these diseases using immunohistochemistry and phosphorylation-dependent and phosphorylation-independent antitau antibodies. The pattern of staining for heparan sulphate and α-synuclein was also investigated. We show that in all of these diseases tau deposits were stained by all antitau antibodies used, with the exception of argyrophilic grains which do not stain with antibody 12E8, confirming our previous findings. Heparan sulphate staining was present to a variable extent in all of these diseases, with the exception of subacute sclerosing panencephalitis, in which no staining was observed. Heparan sulphate staining coexisted with tau staining. In some cases it was more extensive than the tau staining. α-Synuclein staining was present in presynaptic terminals with the exception of one case of Alzheimer's disease, in which α-synuclein-positive Lewy bodies were observed in the hippocampal formation. These findings indicate that tau deposits are antigenically similar in several neurodegenerative diseases and that tau staining is often associated with heparan sulphate staining, supporting the concept that heparan sulphate may be involved in the assembly of tau protein into filaments.
Structure and Pathology of Tau Protein in Alzheimer Disease
International Journal of Alzheimer's Disease, 2012
Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.
Acta Neuropathologica, 2000
Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), and Pick bodies in Pick's disease (PiD) are composed of microtubule-associated protein tau, which is the product of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three-or four-repeat tau isoforms. To study the differential expression of exon 10, we performed double-labeling immunohistochemistry of the hippocampal formation in nine AD, four PSP and three PiD cases. Cryostat sections were processed with and without formic acid (FA) treatment, and double-stained with anti-tau (Alz-50 or PHF-1) or anti-amyloid P component antibodies and one of two specific anti-exon 10 antibodies (E-10). The effect of proteinase-K treatment was also evaluated. The results suggest the following. First, in AD, E-10 immunoreactivity is present in most intracellular NFT, but not in most dystrophic neurites and neuropil threads, suggesting differential expression of tau isoforms in specific cellular domains. Second, in AD, E-10 immunoreactivity is lost or blocked in most extracellular NFT, possibly due to proteolysis. Third, in PSP, E-10 immunoreactivity is hidden or blocked in NFT and tau-positive glial inclusions, but FA treatment exposes the epitope consistent with the hypothesis that PSP inclusions contain four-repeat tau. Fourth, E-10 immunoreactivity is present in dentate fascia NFT in AD and PSP, but not in Pick bodies in the dentate fascia or other areas. The results suggest that expression of exon 10 in tau is specific for cellular domains in a disease-specific manner.
Frontiers in Neurology, 2020
Tau protein (MAPT) is classified as a microtubule-associated protein (MAP) and is believed to regulate the axonal microtubule arrangement. It belongs to the tau/MAP2/MAP4 family of MAPs that have a similar microtubule binding region at their carboxy-terminal half. In tauopathies, such as Alzheimer's disease, tau is distributed more in the somatodendritic compartment, where it aggregates into filamentous structures, the formation of which correlates with cognitive impairments in patients. While microtubules are the dominant interaction partners of tau under physiological conditions, tau has many additional interaction partners that can contribute to its physiological and pathological role. In particular, the amino-terminal non-microtubule binding domain (N-terminal projection region, NTR) of tau interacts with many partners that are involved in membrane organization. The NTR contains intrinsically disordered regions (IDRs) that show a strong evolutionary increase in the disorder and may have been the basis for the development of new, tau-specific interactions. In this review we discuss the functional organization of the tau protein and the special features of the tau non-microtubule binding region also in the connection with the results of Tau KO models. We consider possible physiological and pathological functions of tau's non-microtubule interactions, which could indicate that interactions mediated by tau's NTR and regulated by far-reaching functional interactions of the PRR and the extreme C-terminus of tau contribute to the pathological processes.