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)

Histopathologically, Alzheimer's disease is characterized by plaques and tangles that develop progressively over time. Experimental data described a statin-induced decrease in beta-amyloid production, a major constituent of the plaques. Others reported data on statin-mediated changes in neuronal survival and cytoskeleton, including the microtubule-associated protein tau, a major constituent of the tangles. However, these latter reports remain contradictory. To clarify and extend our knowledge on the effect of statin on the cytoskeleton, we challenged rat primary neuron cultures by lovastatin and determined the metabolite that is critical for structural integrity and survival of neurons. During the blockade of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the neuritic network was affected and eventually was completely destroyed. This process was not part of the execution phase of apoptosis and was marked by alterations in the microfilament and microtubule system. The distribution and phosphorylation of protein tau changed. Immunoblot analysis and indirect immunofluorescence revealed a transient increase in tau phosphorylation, which ceased during the execution of apoptosis. All of these effects could be linked to the lack of the geranylgeranylpyrophosphate intermediate. Inhibition of the geranylgeranylation of Rho family GTPases (geranylgeranyl-transferase I) evoked similar changes in neurons. These data and our findings that statin treatment reduced the membrane-bound fraction of RhoA-GTPase in neurons suggest that reduced levels of functional small G proteins are responsible for the observed effects. Our data demonstrate that lovastatin concentrations able to suppress not only cholesterol but also geranylgeranylpyrophosphate formation may evoke phosphorylation of tau reminiscent of preclinical early stages of Alzheimer's disease and, when prolonged, apoptosis.
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PMID:Blockade of HMG-CoA reductase activity causes changes in microtubule-stabilizing protein tau via suppression of geranylgeranylpyrophosphate formation: implications for Alzheimer's disease. 1253 72

Niemann Pick C (NPC), a fatal autosomal-recessive neurovisceral lipid storage disorder, is a juvenile dementia with massive nerve-cell loss and cytoskeletal abnormalities in cerebral neurons. These abnormalities consist of tangles of tau protein, which is otherwise highly soluble and usually stabilizes the microtubules. Immunologically and ultrastructurally similar tangles are seen some decades later in patients with Alzheimer's disease (AD). There is evidence that tangle-bearing cells in both diseases show higher levels of free (i. e. filipin-positive) cholesterol than adjacent tangle-free nerve cells. The cholesterol accumulates either in a more diffuse way (mainly in AD) or in granule-like accumulations (mainly in NPC). In NPC, neuron cholesterol may originate from sources other than the alimentary tract. Experiments with a NPC mouse model revealed that even in pure neuron cultures, the NPC -/- neurons accumulate free cholesterol in contrast to NPC-wt littermates, suggesting that the cholesterol is either synthesized by the neurons or liberated from degenerated ones before being taken up by the endosomal/lysosomal pathway. The accumulation of free cholesterol in the somata of NPC neurons is associated with a decrease of cholesterol levels in myelin sheaths. In terms of tau protein, NPC -/- mice exhibit higher levels of AT8-positive tau, suggesting that the phosphorylation-dependent mAb AT8 has detected a tau-epitope in a state considered to represent early stages of tangle formation. Concomitantly to the increase in free intracellular cholesterol, the rate-limiting enzyme in cholesterol and isoprenoid biosynthesis, HMG-CoA reductase, was found to be significantly reduced. Experimental blockade of the enzyme's activity by application of the lipid-lowering drug lovastatin showed subcellular shifts in tau phosphorylation as monitored with mAbs AT8, 12E8 and others. In summary, the data showed interesting similarities between NPC and AD suggesting some pathological metabolic pathway in common.
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PMID:Cholesterol and tau protein--findings in Alzheimer's and Niemann Pick C's disease. 1457 25

The products of the Herpes simplex (HSV-1) genome interact with many Alzheimer's disease susceptibility genes or proteins. These in turn affect those of the virus. For example, HSV-1 binds to heparan sulphate proteoglycans (HSPG2), or alpha-2-macroglobulin (A2M), and enters cells via nectin receptors, which are cleaved by gamma-secretase (APH1B, PSEN1, PSEN2, PEN2, NCSTN). The virus also binds to blood-borne lipoproteins and apolipoprotein E (APOE) is able to modify its infectivity. Viral uptake is cholesterol- and lipid raft-dependent (DHCR24, HMGCR, FDPS, RAFTLIN, SREBF1). The virus is transported to the nucleus via the dynein and kinesin (KNS2) motors associated with the microtubule network (MAPT). Amyloid precursor protein (APP) plays a role in this transport. Nuclear export is mediated via disruption of the nuclear lamina and binding to LMNA. Herpes simplex activates kinases (CDC2 and casein kinase 2) whose substrates include APOE, APP, MAPT, PSEN2, and SREBF1. A viral protein is also able to delete mitochondrial DNA, a situation prevalent in Alzheimer's disease. The virus binds to the host transcription factors transcription factor CP2 (TFCP2) and POU2F1 that control many other genes associated with Alzheimer's disease. Viral latency is controlled by IL6 and IL1B and at different stages of its life cycle the virus can either promote or attenuate apoptosis via Fas and tumor necrosis factor pathways (FAS, TNF, DAPK1, PARP1). Viral evasion strategies include inhibition of the antigen processor TAP2, the production of an Fc immunoglobulin receptor mimic (FCER1G) and inhibition of the viral-activated kinase EIF2AK2. These and other host/viral interactions, targeted to certain Alzheimer's disease susceptibility genes, support the idea that some form of synergy between the pathogen and genetic factors may play a role in the pathology of late-onset Alzheimer's disease.
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PMID:Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades. 1816 3

Inhibitors of HMG-CoA reductase (statins) are widely used medications for reduction of cholesterol levels. Statin use significantly reduces risk of cardiovascular disease but has also been associated with lower risk of other diseases and conditions, including dementia. However, some reports suggest that statins also have detrimental effects on the brain. We provide evidence that simvastatin and pravastatin have significantly different effects on expression of genes related to neurodegeneration in astrocytes and neuroblastoma (SK-N-SH) cells in culture. Simvastatin significantly reduced expression of ABCA1 in astrocytes and neuroblastoma cells (by 79% and 97%, respectively; both P < 0.001). Pravastatin had a similar but attenuated effect on ABCA1 in astrocytes (-54%, P < 0.001) and neuroblastoma cells (-70%, P < 0.001). Simvastatin reduced expression of apolipoprotein E in astrocytes (P < 0.01). Furthermore, both statins reduced expression of microtubule-associated protein tau in astrocytes (P < 0.01), while both statins increased its expression in neuroblastoma cells (P < 0.01). In SK-N-SH cells, simvastatin significantly increased cyclin-dependent kinase 5 and glycogen synthase kinase 3beta expression, while pravastatin increased amyloid precursor protein expression. Our data suggest that simvastatin and pravastatin differentially affect expression of genes involved in neurodegeneration and that statin-dependent gene expression regulation is cell type specific.
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PMID:Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells. 1946 Nov 18