Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer disease (AD). Previous studies have shown (i) that in vitro tau can be phosphorylated to an Alzheimer abnormally phosphorylated state-like protein by proline-directed protein kinases MAP kinase and p34cdc2, and (ii) that the AD abnormally phosphorylated tau can be in vitro dephosphorylated by protein phosphatases PP-2B, PP-2A and PP-1 and not by PP-2C. However, to have a direct effect on the regulation of phosphorylation of tau, these enzymes should be present in the affected neurons. In the present study immunocytochemical localization of protein phosphatases PP-1, PP-2A, PP-2B and PTP, and protein kinases MAP kinase and p34cdc2 were studied in the hippocampal formation of AD and as a control in non-demented elderly patients. All the protein phosphatases and protein kinases studied were localized to both granular and pyramidal neurons. In the pyramidal neurons, the enzymes staining was observed in neuronal soma and neurites. PTP-1B, PP-1 and PP-2A were also highly expressed in microglia. The topographical distributions of all the enzymes studied were similar, i.e. the intensity of immunostaining in hippocampus in end-plate (CA3 and CA4) > prosubiculum, subiculum > entorhinal cortex > dentate gyrus > CA2 > CA1. Furthermore, the expression of all the enzymes was also observed in the tangle-bearing neurons. The PP-2B staining of the tangle-bearing neurons was weaker than the unaffected neurons in the same tissue section field in AD cases.
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PMID:Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. 781 92

Ubiquitin-immunoreactive dystrophic neurites in the CA2/3 region of the hippocampus are characteristic of diffuse Lewy body disease (DLBD). The origin of dystrophic CA2/3 neurites is unknown, but their extent correlates with the number of cortical Lewy bodies (LBs). To examine the molecular composition of these lesions, hippocampal sections were obtained at postmortem from cases of DLBD, Parkinson's disease and Alzheimer's disease. The tissue samples were fixed in a variety of fixatives and immunostained with antibodies to ubiquitin, ubiquitin C-terminal hydrolase (PGP9.5), neurofilament protein subunits, tau protein, paired helical filaments and tyrosine hydroxylase (TH). In addition to being ubiquitin positive, both cortical LBs and CA2/3 dystrophic neurites were positive with a neurofilament monoclonal antibody (RM032) and PGP9.5; however, fewer lesions were detected with these antibodies compared to ubiquitin immunocytochemistry. The dystrophic CA2/3 neurites were not stained with antibodies to tau proteins, paired helical filaments or TH. Absence of TH immunoreactivity suggests that CA2/3 neuritic processes are not derived from brain stem dopaminergic afferents to the hippocampus. Since CA2/3 neurites are immunologically similar to cortical LB, the pathogenesis of these lesions may be similar. Characterization of dystrophic CA2/3 neurites and cortical LBs may clarify how these lesions contribute to the emergence of dementia in DLBD.
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PMID:Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. 791 27

Increasing use of immunocytochemistry for evaluation of dementia disorders has revealed histopathological alterations that were previously unknown, even with sensitive silver techniques. Disorders [Pick's disease (PD), diffuse Lewy body disease (DLBD) and corticobasal degeneration (CBD)] in which immunocytochemistry has revealed occult pathology are discussed. All three disorders have neurofilament (NF) immunoreactive neuronal alterations in the neocortex. In DLBD round, eosinophilic cytoplasmic inclusions referred to as cortical Lewy bodies are neurofilament-positive, while in both PD and CBD neurofilament epitopes are expressed in irregularly swollen neurons and their proximal cell processes, which are referred to as ballooned neurons. Interestingly, the cortical neuronal population that is vulnerable to Lewy bodies is similar to that which is vulnerable to ballooned neurons. Furthermore, Lewy bodies can occasionally be detected within the cytoplasm of ballooned neurons. Besides neurofilament-immunoreactivity, Lewy bodies are immunoreactive for ubiquitin, while ballooned neurons are inconsistently stained with antibodies to ubiquitin. Both Lewy bodies and ballooned neurons can be appreciated with routine histology, but they are much easier to detect with immunocytochemistry. In contrast, a new type of neuritic alteration in the hippocampal CA2/3 region has been recognized in DLBD. These dystrophic neurites cannot be appreciated with routine histology and are only optimally seen with immunocytochemistry for ubiquitin. Their presence is a certain indication of the presence of cortical Lewy bodies. The microtuble associated protein tau is the major constituent of neurofibrillary tangles in Alzheimer's disease (AD). Biochemical studies have shown that Pick bodies, argyrophilic neuronal inclusions that are highly characteristic of, if not pathognomonic for PD are also composed of abnormal tau protein. Along with Pick bodies, tau has recently been detected in glial cells in PD. Similar so-called "gliofibrillary tangles" are increasingly recognized in progressive supranuclear palsy. Previously, CBD was considered to be free of such lesions, but recent studies have revealed widespread tau-positive neuronal and glial cytoskeletal lesions in CBD. A distinctive type of tau-positive glial lesion in CBD is characterized by annular clusters of grain-like tau immunoreactivity reminiscent of a neuritic plaque in AD, except that the clusters are devoid of amyloid. The tau-positive profiles are consistently located around a central astrocyte cell body. Double labeling studies with glial fibrillary acidic protein, vimentin and CD44, which are markers for reactive astrocytes, demonstrates tau immunoreactivity within astrocytic processes; these "astrocytic plaques" appear to be specific for CBD. Although NF, ubiquitin and tau proteins are present in diverse neuronal and glial inclusions in these disorders, the morphology and distribution of these lesions differentiate non-AD dementias.
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PMID:Cytoskeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick's disease, and corticobasal degeneration. 884 55

We report the presence of round eosinophilic intranuclear inclusions in a patient with sporadic amyotrophic lateral sclerosis (ALS). The inclusions were limited to the hippocampal pyramidal neurons; they were frequently encountered in the CA1 and CA2 regions and much less frequently in the CA3 and CA4 regions and in the subiculum. Ultrastructurally, they consisted of randomly oriented straight filaments, each about 8-14 nm in diameter, some of which had a tubular appearance in cross-section. Electron-dense, granular material was intermingled with the filaments. Immunohistochemically, all the inclusions were positive for ubiquitin, but were negative for several kinds of cytoskeletal protein, including actin, glial fibrillary acidic protein, vimentin, neurofilament polypeptides, keratin, tubulin, tau protein and microtubule-associated protein 2. To our knowledge, this type of neuronal intranuclear inclusion has not so far been reported in ALS, and its distribution limited to the hippocampal formation is of great interest.
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PMID:Eosinophilic intranuclear inclusions in the hippocampal pyramidal neurons of a patient with amyotrophic lateral sclerosis. 993 Sep 2

A study of brains of 16 dogs from one to 19 years of age showed a structure- and cell-type- specific pattern of tau protein phosphorylation at mAb Tau-1 site and the absence of phosphorylation at the mAb AT8 site. Strong immunolabeling with mAb Tau-1 of the mossy fibers and perikarya of neurons in sectors CA3 and CA4 of the cornu Ammonis, less intensive staining in the cytoplasm in neocortical and subcortical neurons, and selective staining of some pyramidal cells in sectors CA1 and CA2 show differences in the amount of phosphorylated tau, not only in different types of neurons, but also in different parts of the cell. The immunoreactivity of oligodendrocytes and the absence of the reaction in astrocytes reflect differences in tau phosphorylation in glial cells. Marked immunoreactivity in 13 dogs but minimal reaction in brains of three other dogs appears to reflect interindividual differences, which are associated presumably with genetic background. Shrinkage of neurons, tortuosity of mossy fibers, accumulation of phosphorylated tau in the nucleoplasm, and deformation of the nuclei of neurons and oligodendrocytes suggest that excessive phosphorylation at the mAb Tau-1 site is associated with neuronal and oligodendrocyte degeneration and, possibly, cell death.
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PMID:Region- and cell-type-specific pattern of tau phosphorylation in dog brain. 974 20

The cellular distribution of malondialdehyde (MDA) was assessed immunohistochemically in brain specimens from young and normal elderly subjects as well as patients with Alzheimer's disease (AD). MDA was increased in the cytoplasm of neurons and astrocytes in both normal aging and AD, but was rarely detected in normal young subjects. By electron microscopic immunohistochemistry, neuronal MDA formed cap-like linear deposits associated with lipofuscin, while glial MDA deposits surrounded the vacuoles in a linear distribution. In the hippocampus, neuronal and glial MDA deposition was marked in the CA4 region but mild in CA1. By examination of serial sections stained with anti-MDA and antibodies against an advanced glycation end product, N(epsilon)-(carboxymethyl)lysine (CML), neuronal and glial MDA deposition was colocalized with CML in AD, but only neuronal MDA was colocalized with CML in normal aged brains. Glial MDA, although abundant in the aged brain, typically was not colocalized with CML. In AD cases, MDA was colocalized with tau protein in CA2 hippocampal neurons; such colocalization was rare in CA1. MDA also was stained in cores of senile plaques. Thus, while both MDA and CML accumulate under oxidative stress, CML accumulation is largely limited to neurons, in normal aging, while MDA also accumulates in glia. In AD, both MDA and CML are deposited in both astrocytes and neurons.
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PMID:Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer's disease. 1211 53

Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.
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PMID:N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease. 1511 Mar 89

The present study quantified the cleaved form of the microtubule-associated protein tau (cleaved MAP-tau, C-tau), a previously demonstrated marker of CNS toxicity, following the administration of monoamine-depleting regimens of the psychostimulant drugs amphetamine (AMPH), methamphetamine (METH), +/-3,4-methylenedioxymethamphetamine (MDMA), or para-methoxyamphetamine (PMA) in an attempt to further characterize psychostimulant-induced toxicity. A dopamine (DA)-depleting regimen of AMPH produced an increase in C-tau immunoreactivity in the striatum, while a DA- and serotonin (5-HT)-depleting regimen of METH produced an increase in the number of C-tau immunoreactive cells in the striatum and CA2/CA3 and dentate gyrus regions of the hippocampus. MDMA and PMA, two psychostimulant drugs that produce selective 5-HT depletion in the striatum, had no effect on C-tau immunoreactivity in the striatum or hippocampus. Furthermore, 5,7-dihydroxytryptamine (5,7-DHT), an established 5-HT selective neurotoxin, did not produce an increase in C-tau immunoreactivity. Dual fluorescent immunocytochemistry with antibodies to glial fibrillary acidic protein (GFAP) and C-tau indicated that C-tau immunoreactivity was present in astrocytes, not neurons, suggesting that increased C-tau may be an alternative indicator of reactive gliosis. The present results are consistent with previous findings that the DA-depleting psychostimulants AMPH and METH produce reactive gliosis whereas the 5-HT-depleting drugs MDMA and PMA, as well as the known 5-HT selective neurotoxin 5,7-DHT, do not produce an appreciable glial response.
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PMID:The effect of amphetamine analogs on cleaved microtubule-associated protein-tau formation in the rat brain. 1708 36

A case of familial frontotemporal dementia with parkinsonism (FTDP) similar to progressive supranuclear palsy (PSP) was reported. A 58-year-old man developed personality change followed by parkinsonism and dementia. Three family members showed similar symptoms. Cerebral atrophy was marked on the anterior frontotemporal lobes. The substantia nigra, hippocampus, peri-aqueductal gray matter and pontine nucleus were affected with globose neurofibrillary tangles (NFT) and glial tangles. Argyrophilic grains were distributed in the CA1-CA2. NFT, glial tangles and argyrophilic grains expressed four-repeat microtubule-associated protein tau (MAPT). MAPT gene had no mutation. Familial occurrence of FTDP with PSP-like tauopathy is rare.
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PMID:Subcortical neurofibrillary tangles and argyrophilic grains in a case of familial frontotemporal dementia with parkinsonism. 1834 25

3,4-Methylenedioxymethamphetamine (MDMA) ("Ecstasy") produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. We examined whether MDMA induces increases in tau protein phosphorylation, which are typically associated with Alzheimer's disease and other chronic neurodegenerative disorders. We injected mice with MDMA at cumulative doses of 10-50 mg/kg intraperitoneally, which are approximately equivalent to doses generally consumed by humans. MDMA enhanced the formation of reactive oxygen species and induced reactive gliosis in the hippocampus, without histological evidence of neuronal loss. An acute or 6 d treatment with MDMA increased tau protein phosphorylation in the hippocampus, revealed by both anti-phospho(Ser(404))-tau and paired helical filament-1 antibodies. This increase was restricted to the CA2/CA3 subfields and lasted 1 and 7 d after acute and repeated MDMA treatment, respectively. Tau protein was phosphorylated as a result of two nonredundant mechanisms: (1) inhibition of the canonical Wnt (wingless-type MMTV integration site family) pathway, with ensuing activation of glycogen synthase kinase-3beta; and (2) activation of type-5 cyclin-dependent kinase (Cdk5). MDMA induced the expression of the Wnt antagonist, Dickkopf-1, and the expression of the Cdk5-activating protein, p25. In addition, the increase in tau phosphorylation was attenuated by strategies that rescued the Wnt pathway or inhibited Cdk5. Finally, an impairment in hippocampus-dependent spatial learning was induced by doses of MDMA that increased tau phosphorylation, although the impairment outlasted this biochemical event. We conclude that tau hyperphosphorylation in the hippocampus may contribute to the impairment of learning and memory associated with MDMA abuse.
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PMID:Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine ("Ecstasy"). 1835 27


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