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)

Human ApoE is a plasma and cerebrospinal fluid protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, appears to be involved in the transport of cholesterol and other lipids among the nervous cells. ApoE is synthesized by astrocytes in brain and by macrophages in peripheral nerves during the repair response to tissue injury and regeneration. In the nervous system ApoE may also be involved in processes unrelated to lipid transport, the processes that were completely unsuspected until very recently and have led to the link between ApoE and the neurodegenerative disorder--Alzheimer's disease. The lipoprotein has been found in association with cerebral amyloid deposits and the presence of the epsilon 4 allele constitutes a major genetic risk factor for Alzheimer's disease but does not influence the rate of cognitive decline. It has been shown that ApoE4 promotes fibrillogenesis in vivo and in vitro from amyloid beta peptide and ApoE3 binds to tau protein slowing the initial rate of its phosphorylation and self-assembling into paired helical filaments. This review summarizes the data leading to this conclusion and discusses possible mechanisms: of ApoE involvement based on recent biochemical studies. The clinical application of ApoE level estimation in cerebrospinal fluid and phenotyping is presented.
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PMID:[Apolipoprotein E function in the nervous system]. 963 84

Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid beta protein (Abeta1-42). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3beta (GSK-3beta). Deletion studies show that both tau and GSK-3beta bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3beta into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3beta. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3beta with mutant PS1 leads to increased phosphorylation of tau.
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PMID:Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. 968 33

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.
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PMID:Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. 977 46

According to the amyloid hypothesis for the pathogenesis of Alzheimer's disease (AD), amyloid beta peptide (Abeta) directly affects neurons, leading to neurodegeneration and tau phosphorylation, followed by the production of paired helical filaments (PHF) in neurofibrillary tangles (NFT). To analyze the relationship between the phosphorylation sites of tau and the activation of kinases in response to Abeta, we treated cultured rat hippocampal neurons with a peptide fragment of Abeta, Abeta(25-35). Abeta(25-35) treatment activated tau protein kinase I/glycogen synthase kinase-3beta (TPKI/GSK-3beta) but not glycogen synthase kinase-3alpha (GSK-3alpha) or mitogen activated protein kinase (MAP kinase) in primary culture of hippocampal neurons. Using antibodies that recognize phosphorylated sites of tau, we showed that tau phosphorylation was enhanced in at least five sites (Ser199, Ser202, Ser396, Ser404, and Ser413 numbered according to the human tau isoform containing 441 amino acid residues), to an extent that depended on the level of TPK I/GSK-3beta. Treatment with TPK I/GSK-3beta antisense oligonucleotide inhibited the enhancement of tau phosphorylation induced by Abeta(25-35) exposure. Thus, TPK I/GSK-3beta activation by Abeta(25-35) may lead to extensive tau phosphorylation.
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PMID:Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. 980 90

Histopathological features of Alzheimer's disease (AD) include extracellular deposits of amyloid beta (A beta) fibrils in the cores of senile plaques, intracellular neurofibrillary tangles (NFT) which are composed of paired helical filaments (PHF), and neuronal cell loss. The main component of PHF is highly phosphorylated tau protein. We identified a protein kinase converting normal tau into a PHF-like state. The kinase is tau protein kinase (TPK) I/glycogen synthase kinase (GSK)-3 beta. Using a neuronal cell culture system as an AD model, it was recognized that TPK I/GSK-3 beta plays a central role in AD pathology. We hypothesize that A beta-induced neuronal cell death occurs by the following mechanism. A beta inactivates PI3-kinase and activates TPK I/GSK-3 beta, which in turn phosphorylates and inactivates both tau and pyruvate dehydrogenase (PDH). After the ability of tau to promote microtubule assembly is diminished by phosphorylation, soluble tau molecules aggregate into PHF by an unknown mechanism. Destabilization of microtubule arrays causes inhibition of axonal transport and accumulation of amyloid precursor protein (APP). Phosphorylation of PDH inhibits the reaction converting pyruvate to acetyl-CoA, resulting in inhibition of energy metabolism and a decrease in acetylcholine, both of which are also characteristics of AD. These changes may lead to neuronal cell death.
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PMID:[Involvement of tau protein kinase in amyloid-beta-induced neurodegeneration]. 981 11

This study examines the evolution of Alzheimer's disease (AD)-related pathology in a subcortical predilection site, the basal nucleus of Meynert (bnM), which is a major source of cortical cholinergic innervation. Brains of 51 autopsy cases were studied using silver techniques and immunostaining for tau-associated neurofibrillary pathology and for amyloid beta protein (Abeta) deposits. All cases are classified according to a procedure permitting differentiation of six stages of AD-related neurofibrillary changes in the cerebral cortex. Initial cytoskeletal abnormalities in the bnM are already noted in stage I of cortical neurofibrillary changes. The gradual development of the neurofibrillary pathology in the bnM parallels the progression of the AD-related stages in the cerebral cortex. A variety of morphologically distinguishable cytoskeletal alterations are observed in large nerve cells which predominate in the bnM. Based on these cellular alterations, a sequence of cytoskeletal deterioration is proposed. Initially, the abnormal tau protein is distributed diffusely throughout the cell body and the neuronal processes. Subsequently, it aggregates to form a neurofibrillary tangle, which appears as a spherical somatic inclusion. The cell processes gradually become fragmented. Finally the parent cell dies, leaving behind an extraneuronal "ghost tangle". With regard to the cortical stages of AD-related neurofibrillary changes, the initial forms of cytoskeletal changes in the bnM predominate in the transentorhinal AD stages (I and II), while "ghost tangles" preferentially occur in the neocortical stages (V and VI). The considerable morphological diversity of cytoskeletal alterations is typical of stages III and IV. These results indicate that individual neurons of the bnM enter the sequence of cytoskeletal deterioration at different times.
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PMID:Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert. 1096 95

Mutations in presenilin genes are linked to early onset familial Alzheimer's disease (FAD). Previous work in non-neuronal cells indicates that presenilin-1 (PS1) associates with cytoskeletal elements and that it facilitates Notch1 signaling. Because Notch1 participates in the control of neurite growth, cultured hippocampal neurons were used to investigate the cytoskeletal association of PS1 and its potential role during neuronal development. We found that PS1 associates with microtubules (MT) and microfilaments (MF) and that its cytoskeletal association increases dramatically during neuronal development. PS1 was detected associated with MT in the central region of neuronal growth cones and with MF in MF-rich areas extending into filopodia and lamellipodia. In differentiated neurons, PS1 mutations reduced the interaction of PS1 with cytoskeletal elements, diminished the nuclear translocation of the Notch1 intracellular domain (NICD), and promoted a marked increase in total neurite length. In developing neurons, PS1 overexpression increased the nuclear translocation of NICD and inhibited neurite growth, whereas PS1 mutations M146V, I143T, and deletion of exon 9 (D9) did not facilitate NICD nuclear translocation and had no effect on neurite growth. In cultures that were treated with amyloid beta (Abeta), PS1 mutations significantly increased neuritic dystrophy and AD-like changes in tau such as hyperphosphorylation, release from MT, and increased tau protein levels. We conclude that PS1 participates in the regulation of neurite growth and stabilization in both developing and differentiated neurons. In the Alzheimer's brain PS1 mutations may promote neuritic dystrophy and tangle formation by interfering with Notch1 signaling and enhancing pathological changes in tau.
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PMID:Presenilin-1 mutations reduce cytoskeletal association, deregulate neurite growth, and potentiate neuronal dystrophy and tau phosphorylation. 1115 69

Immunoreactivities of total apolipoprotein E (ApoE-IR), amyloid beta peptide(1-42) (Abeta42-IR), interleukin-6 (IL-6-IR), substance P (SPIR) and total tau protein (TTIR) were measured in lumbar cerebrospinal fluid samples of patients with Alzheimer's disease (AD), non-Alzheimer's dementias (NAD), neurological disorders without cognitive impairment (OND) and controls without central nervous system disease using sensitive and specific enzyme immunoassay methods. TTIR was highly significantly increased (P < 0,001) and Abeta42-IR was significantly decreased (P < 0,001 vs. OND/CO, P < 0,03 vs. NAD) in the AD cohort compared with the other diagnostic groups. Significant increases in AD were also found for ApoE-IR (P < 0,001) and IL-6 (P < 0,03), but there was a considerable overlap between groups. In the total AD cohort, SPIR was not significantly changed, but AD patients with late disease onset (>65 years) showed significantly higher values than both early onset patients (<65 years) and controls (P < 0,05). Discriminant function analysis showed that Abeta42-IR (cut-off value 375pg/ml) and TTIR (cut-off value 440 pg/ml) levels contributed most to the group classification of patients. At 85% sensitivity for AD and 100% specificity for controls, the combined evaluation of Abeta42-IR and TTIR in this cross-sectional study resulted in a graph separating AD from non-AD patients with increased specificity of 91% and 75% for AD versus OND and NAD, respectively.
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PMID:Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients. 1131 76

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.
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PMID:Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype. 1137 23

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.
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PMID:The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. 1241 5


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