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)

Alzheimer's disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL-CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.
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PMID:Phenotypic profiles and functional genomics in Alzheimer's disease and in dementia with a vascular component. 1526 64

Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies.
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PMID:Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. 1697 41

Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
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PMID:Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review. 3038 71

Mercury is one of the most toxic elements and causes a multitude of health problems. It is ten times more toxic to neurons than lead. This study was created to determine if mercury could be causing Alzheimer's disease (AD) by cross referencing the effects of mercury with 70 factors associated with AD. The results found that all these factors could be attributed to mercury. The hallmark changes in AD include plaques, beta amyloid protein, neurofibrillary tangles, phosphorylated tau protein, and memory loss-all changes that can be caused by mercury. Neurotransmitters such as acetylcholine, serotonin, dopamine, glutamate, and norepinephrine are inhibited in patients with Alzheimer's disease, with the same inhibition occurring in mercury toxicity. Enzyme dysfunction in patients with Alzheimer's disease include BACE 1, gamma secretase, cyclooxygenase-2, cytochrome-c-oxidase, protein kinases, monoamine oxidase, nitric oxide synthetase, acetyl choline transferase, and caspases, all which can be explained by mercury toxicity. Immune and inflammatory responses seen in patients with Alzheimer's disease also occur when cells are exposed to mercury, including complement activation, cytokine expression, production of glial fibrillary acid protein antibodies and interleukin-1, transforming growth factor, beta 2 microglobulins, and phosphodiesterase 4 stimulation. Genetic factors in patients with Alzheimer's disease are also associated with mercury. Apolipoprotein E 4 allele increases the toxicity of mercury. Mercury can inhibit DNA synthesis in the hippocampus, and has been associated with genetic mutations of presenilin 1 and 2, found in AD. The abnormalities of minerals and vitamins, specifically aluminum, calcium, copper, iron, magnesium, selenium, zinc, and vitamins B1, B12, E, and C, that occur in patients with Alzheimer's disease, also occur in mercury toxicity. Aluminum has been found to increase mercury's toxicity. Likewise, similar biochemical factors in AD are affected by mercury, including changes in blood levels of homocysteine, arachidonic acid, DHEA sulfate, glutathione, hydrogen peroxide, glycosamine glycans, acetyl-L carnitine, melatonin, and HDL. Other factors seen in Alzheimer's disease, such as increased platelet activation, poor odor identification, hypertension, depression, increased incidences of herpes virus and chlamydia infections, also occur in mercury exposure. In addition, patients diagnosed with Alzheimer's disease exhibit higher levels of brain mercury, blood mercury, and tissue mercury in some studies. The greatest exogenous sources of brain mercury come from dental amalgams. Conclusion: This review of the literature strongly suggests that mercury can be a cause of Alzheimer's Disease.
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PMID:A Hypothesis and Evidence That Mercury May be an Etiological Factor in Alzheimer's Disease. 3186 Oct 93