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)

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimer's disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimer's disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes. 747 10

In this clinical study the cerebrospinal fluid (CSF) level of a novel form of the beta-amyloid peptide (A beta) extending to position 42 (A beta 42) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF A beta 42 levels, total A beta peptides, microtubule-associated protein tau, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF A beta 42 levels were found to be significantly lower in AD patients relative to controls, whereas total A beta levels were not. A beta 42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, tau levels were increased in AD patients; however, neither A beta 42 nor tau levels were apparently influenced by the ApoE genotype.
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PMID:Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. 757 61

Cerebrospinal fluid from 70 patients with Alzheimer's disease (AD) and 96 patients with non-AD neurological diseases as well as 19 normal control subjects was surveyed by sandwich enzyme-linked immunosorbent assay to quantitate levels of the microtubule-associated protein tau in cerebrospinal fluid. The tau level was significantly increased in AD patients as compared with that in patients with non-AD neurological diseases and control subjects. Increased tau levels were found irrespective of age at onset, apolipoprotein E genotype, and clinical stage. Western blots of AD cerebrospinal fluid proteins revealed two to three tau-immunoreactive bands with an apparent molecular mass between 50 and 65 kd consistent with phosphorylated cerebrospinal fluid tau. Taken together, our results suggest that cerebrospinal fluid tau might reflect the progressive accumulation of altered tau due to the progressive death of neurons in the AD brain, and that the enzyme-linked immunosorbent assay of cerebrospinal fluid tau may prove to be a reliable and early diagnostic test for AD.
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PMID:Tau in cerebrospinal fluid: a potential diagnostic marker in Alzheimer's disease. 757 62

Alzheimer's disease (AD) is rapidly moving from the obscure category of degenerative diseases to the more precise one of metabolic disorders. Recent discoveries have substantiated the hypothesis that AD results from the deposition of beta-amyloid, which is formed by polymers of a proteolytic fragment of the amyloid protein precursor (APP), and may induce intraneuronal aggregation of the microtubule-associated protein tau into paired helical filaments and neuronal death. There is also evidence that AD is a heterogeneous age-related disorder of multifactorial origin, which may arise as a consequence of point mutations of genes encoding APP or other proteins involved in its metabolism (familial AD), or a combination of genetic and non-genetic factors (sporadic AD). Familial AD displays genetic and phenotypic heterogeneity, meaning that mutations of different genes may cause the AD phenotype, and that different mutations of the same gene may cause phenotypically distinct disorders, including Alzheimer-type dementia and cerebral amyloid angiopathy with cerebral hemorrhages and stroke. On the other hand, aging, gender, head trauma, and variants of the apolipoprotein E gene have been shown to increase the risk of developing the more prevalent sporadic form of AD. The mechanisms by which these factors influence amyloidogenesis are beginning to be understood, and this will provide a rational basis for future therapy. Knowledge of the molecular basis of AD would eventually allow accurate risk prediction before the disease becomes clinically apparent, and better chances for early treatment and prevention.
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PMID:Alzheimer's disease, beta-amyloidosis, and aging. 769 97

Inheritance of specific apolipoprotein E (apoE) alleles determines, in large part, the risk and mean age of onset of late-onset familial and sporadic Alzheimer disease. The mechanism by which the apoE isoforms differentially contribute to disease expression is, however, unknown. Isoform-specific differences have been identified in the binding of apoE to the microtubule-associated protein tau, which forms the paired helical filament and neurofibrillary tangles, and to amyloid beta peptide, a major component of the neuritic plaque. These and other isoform-specific interactions of apoE give rise to testable hypotheses for the mechanism(s) of pathogenesis of Alzheimer disease. An unresolved issue of increasing importance is the relationship between the structural pathological lesions and the cellular pathogenesis responsible for the clinical disease phenotype, progressive dementia. The identification of apoE in the cytoplasm of human neurons and the characterization of isoform-specific binding of apoE to the microtubule-associated proteins tau and MAP-2 present the possibility that apoE may affect microtubule function in the Alzheimer brain.
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PMID:Apolipoprotein E and Alzheimer disease. 776 90

The initial report on APOE as a susceptibility gene for late-onset Alzheimer's disease was presented a little more than two years ago. During the past year, several significant events have given added impetus to research into Alzheimer's. The association of increased allele frequency of APOE4 with Alzheimer's disease has been reproduced in several dozen laboratories around the world. The protective effect of the APOE2 allele has been reported and also rapidly verified. No evidence exists to support the notion of linkage disequilibrium with any nearby locus on chromosome 19. The neuropathological demonstration of apolipoprotein E (apoE) within neuronal cytoplasm in a location suitable for proposed interaction with microtubule-associated protein tau and MAP2c has introduced a new view of neuronal neurobiology. As apoE is not known to be expressed in neurons, its relationship with cellular receptors, such as the low-density lipoprotein related receptor, and the mechanism of intracellular trafficking are now important research problems. The role of apoE as a metabolic co-factor in neuronal metabolism presents new possibilities for neuronal mechanisms of maintenance and response to stress.
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PMID:APOE is a major susceptibility gene for Alzheimer's disease. 776 50

Alzheimer's disease, the most common cause of dementia in the elderly, is rapidly becoming epidemic in the western world, with major social and economic ramifications. Thus enormous international scientific efforts are being made to increase our understanding of the pathogenesis of this disease, with the eventual goal of developing beneficial therapy. The two major neuropathological hallmarks of Alzheimer's disease (AD) are extracellular senile plaques, the principal component of which is the A beta amyloid peptide, and intraneuronal neurofibrillary tangles, which are composed of aggregated tau protein in the form of paired helical filaments (PHF). In the past decade, since the major proteinaceous components of these pathological markers have been identified, great strides have been made in elucidating the biochemical processes which may underlie their abnormal deposition and aggregation in Alzheimer's disease. Simultaneously, extensive population genetic analyses have identified mutations in the A beta amyloid precursor protein (APP) in a small number of pedigrees with familial Alzheimer's disease (FAD) whilst other FAD cases have been linked to an, as yet, unidentified marker on chromosome 14. Most recently, inheritance of the type 4 allele of apolipoprotein E has also been identified as a risk factor in sporadic AD. The challenge facing scientists now is to incorporate this wealth of exciting new biochemical and genetic data into a coherent model which can explain the long established neurochemical and histopathological lesions characteristic of AD.
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PMID:Dorothy Russell Memorial Lecture. The molecular pathology of Alzheimer's disease: are we any closer to understanding the neurodegenerative process? 780 82

The apolipoprotein E type 4 allele is a susceptibility gene for late-onset Alzheimer's disease. Apolipoprotein E is found in neurons, some of which contain paired helical filaments made of the microtubule-associated protein tau. Previous studies have demonstrated that the apoE3 isoform, but not the apoE4 isoform, binds tau with high avidity. Because the microtubule-associated protein MAP2c also effects microtubule assembly and stability, we examined interactions between apoE isoforms and MAP2c. Similar to the tau-binding results, apoE3, but not apoE4, bound MAP2c. Binding was detectable down to 10(-9) M MAP2c and 10(-8) M apoE3. Isoform-specific interactions of apoE with the microtubule-associated proteins MAP2c and tau might affect intracellular maintenance of microtubules and could contribute to a time-dependent pathogenesis of Alzheimer's disease.
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PMID:Isoform-specific interactions of apolipoprotein E with the microtubule-associated protein MAP2c: implications for Alzheimer's disease. 789 87

The apolipoprotein E (apoE) type 4 allele (APOE4) is a susceptibility gene for late-onset familial and sporadic Alzheimer disease. ApoE is found in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease. Neurofibrillary tangles contain paired helical filaments formed from hyperphosphorylated microtubule-associated protein tau. In vitro, tau binds avidly to apoE3, but not to apoE4, forming a bimolecular complex. Tau phosphorylated with a brain extract does not bind either isoform. ApoE3 binds to the microtubule-binding repeat region of tau, which is also the region that is thought to cause self-assembly into the paired helical filament. Binding studies with fragments of ApoE demonstrate that the tau-binding region of apoE3 corresponds to its receptor-binding domain and is distinct from the region that binds lipoprotein particles or beta/A4 peptide. Isoform-specific interactions of apoE with tau may regulate intraneuronal tau metabolism in Alzheimer disease and alter the rate of formation of paired helical filaments and neurofibrillary tangles.
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PMID:Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. 797 31

A genetic classification of Alzheimer disease(s) (AD) is presented. We describe a potential metabolic process in individuals who inherit apolipoprotein E-epsilon 4 (APOE4, gene; apoE4, protein) alleles, leading to increased risk and earlier age of onset of late-onset Alzheimer disease. Apolipoprotein E-epsilon 3 (apoE3) binds to tau protein, possibly slowing the initial rate of tau phosphorylation and self-assembly into paired helical filaments (PHFs); apoE4 does not bind tau. Tau promotes microtubule assembly and stabilizes microtubules; hyperphosphorylated tau does not bind, thereby destabilizing microtubules. Hyperphosphorylated tau may self-assemble into PHFs. Over time a bias toward destabilization of microtubules and the formation of neurofibrillary tangles may occur in individuals who inherit APOE4 alleles, leading to a shorter functional neuronal life span. This hypothesis focuses attention on two important aspects of AD research design: (1) Although the inheritance of APOE4 is associated with increased risk and decreased age of onset, apoE4 does not directly cause the disease. Our data point to the absence of an important function of apoE3 or apoE2 in individuals who do not inherit these alleles as the genetically relevant metabolic factor. This has important implications for design of experiments directed toward understanding the relevant neuronal metabolism. (2) Should this hypothesis be proven and confirmed, targets for pharmaceutical therapy designed to mimic the metabolic function of apoE3 or apoE2 become a realistic preventive strategy.
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PMID:Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. 831 35


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