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

Neuronal excitation involving the excitatory glutamate receptors is recognized as an important underlying mechanism in neurodegenerative disorders. Excitation resulting from stimulation of the ionotropic glutamate receptors is known to cause the increase in intracellular calcium and trigger calcium-dependent pathways that lead to neuronal apoptosis. Kainic acid (KA) is an agonist for a subtype of ionotropic glutamate receptor, and administration of KA has been shown to increase production of reactive oxygen species, mitochondrial dysfunction, and apoptosis in neurons in many regions of the brain, particularly in the hippocampal subregions of CA1 and CA3, and in the hilus of dentate gyrus (DG). Systemic injection of KA to rats also results in activation of glial cells and inflammatory responses typically found in neurodegenerative diseases. KA-induced selective vulnerability in the hippocampal neurons is related to the distribution and selective susceptibility of the AMPA/kainate receptors in the brain. Recent studies have demonstrated ability of KA to alter a number of intracellular activities, including accumulation of lipofuscin-like substances, induction of complement proteins, processing of amyloid precursor protein, and alteration of tau protein expression. These studies suggest that KA-induced excitotoxicity can be used as a model for elucidating mechanisms underlying oxidative stress and inflammation in neurodegenerative diseases. The focus of this review is to summarize studies demonstrating KA-induced excitotoxicity in the central nervous system and possible intervention by anti-oxidants.
 ...
PMID:Kainic acid-mediated excitotoxicity as a model for neurodegeneration. 1595 8

The abnormal hyperphosphorylation of tau protein in brain is attributed to a number of neurodegenerative diseases such as Alzheimer disease. It has been reported that cold water stress (CWS) could cause rapid reversible tau phosphorylation in brain. To explore the possible long-tem effects of CWS on tau phosphorylation, we employed the immunoblot and immunohistochemical methods to analyze the phosphorylation of tau in the hippocampus of mice subjected to CWS. Results showed that CWS stimulation caused not only an early phase reversible tau phosphorylation, but also a later phase tau phosphorylation after 6h. The distribution pattern of phosphorylated tau (P-tau) in the later phase was different to that of early phase. At 1h after CWS, defined as early phase, P-tau was strikingly located in the mossy fibers and nerve terminals at the molecular layer of dentate gray (DG), whereas at 12h, defined as later phase, P-tau was dominantly located in the somatodendritic compartments of neurons in DG and CA3/CA1 regions, but obviously decreased in the mossy fibers and nerve terminals of molecular layer. These findings demonstrate that CWS leads to prominent changes of tau phosphorylation and P-tau localization in the hippocampus in a time dependent manner.
 ...
PMID:Dynamic changes of phosphorylated tau in mouse hippocampus after cold water stress. 1600 67

Protein misfolding is a distinguishing feature of a number of neurodegenerative diseases. Accumulation of misfolded protein often results in cellular lesions, the location of lesions correlating with the nature of symptoms. Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Pick's Disease (PiD) all present with pathological lesions containing hyperphosphorylated filamentous tau protein; however, the location and type of lesion varies. In addition, granulovacuolar degeneration (GVD) bodies have been reported within hippocampal pyramidal neurons in AD, PSP, CBD and PiD tissue. GVDs are defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. We have previously reported that the phosphorylated form of stress-activated protein kinase/c-Jun N-terminal kinase (p-SAPK/JNK) accumulates in granules within hippocampal pyramidal cell bodies in AD tissue at the time that hyperphosphorylated tau begins to aggregate into early-stage NFTs. We now report that p-SAPK/JNK granules are found within the hippocampal CA1 region of PSP, CBD and PiD cases as well and that these granules are likely GVD bodies. Quantitatively, p-SAPK/JNK granules and GVDs are found in comparable numbers of CA1 cells. Within cells, p-SAPK/JNK granules are distributed throughout the cytoplasm in a manner similar to the distribution of GVDs and a subset of granules co-localize with GVD markers. Ultrastructurally, p-SAPK/JNK granules are located in large cytoplasmic vacuoles, thereby fitting the definition of a GVD body. With the implication of granular p-SAPK/JNK as a marker of GVDs, our study strongly suggests that a heterogeneous group of proteins form GVDs. The mechanism of GVD formation is therefore an interesting one, and is likely separate and distinct from the mechanism of tau inclusion formation.
 ...
PMID:Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer's disease and tauopathies to granulovacuolar degeneration bodies. 1708 32

Hippocampal sclerosis (HpScl) is characterized by neuronal loss and gliosis in CA1 and subiculum of the hippocampus, and may be one contributing factor to dementia in old age. The term hippocampal sclerosis dementia (HpSclD) designates the presence of both hippocampal sclerotic lesions and a dementia syndrome. In the present review, we outline the pathological heterogeneity underlying HpSclD and discuss related disorders due to tau protein pathology and frontotemporal dementia with ubiquitin positive inclusions (FTLD-U). We also provide a detailed morphological description of ten of our own autopsied HpSclD cases, and compare these pathological findings with those reported in the literature. The lateralization of HpScl and the atrophy of the mammillary bodies were striking features in most of our cases. The main pathology consisted of tau positive lesions with a predominance of neuronal and glial pretangles in Ammon's horn and the dentate gyrus. Neurofibrillary and ghost tangles in CA1 and the subiculum were scarce and thus insufficient to explain the hippocampal pyramidal cell loss. In some cases, tau pathology in the hippocampal formation coexisted with glial tau pathology in the frontal cortex. The most striking finding besides the tau pathology was the presence of concomitant neuronal cytoplasmic inclusions and neurites immunoreactive for the transactive response DNA-binding protein-43 (TDP-43) in the dentate gyrus and temporal neocortex, similar to those found in FTLD-U. Taken together, the pathology of HpSclD is indicative of a degenerative rather than a hypoxic/ischemic etiology of HpSclD. Presently, HpSclD may best be deemed a disorder with various neurodegenerative etiologies, most notably tauopathy and TDP-43 proteinopathy (i.e. FTLD-U). Each of these disease processes could either independently or concertedly account for the dementia syndrome in HpSclD.
 ...
PMID:Hippocampal sclerosis dementia: a reappraisal. 1763 26

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.
 ...
PMID:Subcortical neurofibrillary tangles and argyrophilic grains in a case of familial frontotemporal dementia with parkinsonism. 1834 25

We have previously demonstrated in a transgenic rat model of tauopathy that human misfolded truncated tau derived from Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. We employed this model to investigate the impact of truncated tau expression levels on life span, neuronal loss and the final load of neurofibrillary tangles (NFTs) in transgenic rats. Two independent transgenic lines (SHR72, SHR318), that display different expression levels of truncated tau, were utilized in this study. We found that transgene expression levels in the brain of SHR72 rats were 44% higher than in SHR318 rats and that truncated tau protein levels determined the survival rate of transgenic rats. The line with higher expression levels of truncated tau (SHR72) showed decreased median survival (222.5 days) when compared with the line with lower expression (SHR318; 294.5 days). Interestingly, NFT loads (total NFT/total neurons) were very similar in terminal stages of disease in both transgenic lines (SHR72 - 10.9%; SHR318 - 11.6%), despite significantly different expression levels of truncated tau. Moreover, mean neuron numbers in the hippocampus (CA1-3) and brain stem (gigantocellular reticular nucleus) in the two transgenic rat strains in the terminal stages of disease were similar, and did not differ significantly from those observed in age-matched non-transgenic controls. These findings suggest that the expression levels of misfolded truncated tau determine the life span in a transgenic rat model of tauopathy without causing neuronal loss or correlating with terminal NFT load.
 ...
PMID:Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. 1870 95

Glycogen synthase kinase-3beta (GSK-3beta) has been proposed as the main kinase able to phosphorylate tau aberrantly in Alzheimer's disease and in related tauopathies. We have previously generated a double transgenic mouse line overexpressing the enzyme GSK-3beta and tau protein carrying a triple frontotemporal dementia and parkinsonism linked to chromosome 17 mutation whose expression patterns overlap in CA1 (pyramidal neurons) and dentate gyrus (granular neurons). Here, we have used this transgenic model to analyze how axonal and somatodendritic neuronal compartments are affected in the hippocampus. Our data demonstrate that neuronal subpopulations respond differentially to increased GSK-3 activity. Thus, dentate gyrus granular neurons undergo apoptotic death with subsequent degeneration of the mossy fibers, while CA1 pyramidal neurons accumulate hyperphosphorylated tau both in the axonal and in the somatodendritic compartments. These studies also allow us to propose a model of spreading of pathology through the hippocampus as a consequence of GSK-3 and tau dysregulation.
 ...
PMID:Hippocampal neuronal subpopulations are differentially affected in double transgenic mice overexpressing frontotemporal dementia and parkinsonism linked to chromosome 17 tau and glycogen synthase kinase-3beta. 1895 53

It is shown that l-3-n-butylphthalide (l-NBP), the isomer of dl-NBP (racemic 3-n-butylphthalide, a new anti-cerebral ischemic agent) significantly attenuated cerebral hypoperfusion-induced learning dysfunction and brain damage in rats. In the present study, l-NBP (10 and 30 mg/kg) long-term (3-month) treatment of aged rat (21-month-old) significantly improved the learning and memory capability measured by the Morris water maze test. Hematoxylin-eosin-stained slices showed that both l-NBP at 30 mg/kg, and memantine as control at 20 mg/kg, attenuated the neurodegenerative changes in aged rats. L: -NBP treatment significantly increased the choline acetyltransferase activity and dose-dependently decreased the acetylcholinesterases activity in the hippocampus of aged rats. The immunohistological study demonstrated that expressions of beta-secretase and hyperphosphorylated tau protein were significantly increased in the hippocampus CA1 subfield and parietal cortex in aged rats. However, they were decreased significantly by treatment of l-NBP and memantine for 3 months. Our results indicated that long-term treatment with l-NBP might prevent age-related neurodegenerative changes by modulation of cholinergic system, reduction of phosphorylated tau and maintain structure and morphology of neurons. Therefore, l-NBP might be a potential drug for treatment of senile dementia.
 ...
PMID:Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats. 1921 78

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.
 ...
PMID:Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study. 1932 62

We investigated a possible role in Alzheimer's disease (AD) for FKBP12, a peptidyl-prolyl cis-trans isomerase known to be important in protein assembly, folding and transportation by using Western blotting and microscopic analyses in postmortem brain tissues from elderly controls and the patients with AD. FKBP12 was enriched and localized to neuronal cell bodies and neurites in control brains. Intense immunoreactivity was found in large neurons such as pyramidal cells. Many FKBP12 positive granules were located in the cytoplasm and the proximal portion of dendrites and axons, and in the nuclei. By contrast, the expression of FKBP12 in AD brains was lower than in control brains. Furthermore, numerous intracellular neurofibrillary tangles (NFTs) were stained for FKBP12 in the hippocampal CA1 subfield, subiculum, entorhinal cortex and angular gyrus. Neuritic pathology such as neuropil threads and dystrophic neurites (DNs) within senile plaques (SPs) and some reactive astrocytes were also immunolabeled for FKBP12 in AD. Double immunofluorescence staining showed dual labeling of intracellular NFTs for FKBP12 and tau. Similar results were obtained in reactive astrocytes for the combination of FKBP12 and glial fibrillary acidic protein (GFAP). Labeling for FKBP12 was dense in axons stained for highly phosphorylated neurofilament protein. Thus our results suggest that FKBP12 may be involved in neuronal or astrocytic cytoskeletal organization and in the abnormal metabolism of tau protein in AD damaged neurons.
 ...
PMID:A peptidyl-prolyl isomerase, FKBP12, accumulates in Alzheimer neurofibrillary tangles. 1941 59


<< Previous 1 2 3 4 5 6 7 Next >>