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10.1186/alzrt245 http://scihub22266oqcxt.onion/10.1186/alzrt245 C4055000!4055000!24625058     free     free     free Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Alzheimers+Res+Ther 2014 ; 6 (2): 15 Nephropedia Template TP {{tp|p=24625058|t=2014. Platelet-activating factor antagonists enhance intracellular degradation of amyloid-?42 in neurons via regulation of cholesterol ester hydrolases |pdf=|usr=}}{{24625058}} gab.com Text Platelet-activating factor antagonists enhance intracellular degradation of amyloid- 42 in neurons via regulation of cholesterol ester hydrolases JO: Alzheimers Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=24625058 #FOAvip Introduction: The progressive dementia that is characteristic of Alzheimer?s disease is associated with the accumulation of amyloid-beta (A?) peptides in extracellular plaques and within neurons. A? peptides are targeted to cholesterol-rich membrane micro-domains called lipid rafts. Observations that many raft proteins undertake recycling pathways that avoid the lysosomes suggest that the accumulation of A? in neurons may be related to A? targeting lipid rafts. Here we tested the hypothesis that the degradation of A? by neurons could be increased by drugs affecting raft formation. Methods: Primary neurons were incubated with soluble A? preparations. The amounts of A?42 in neurons or specific cellular compartments were measured by enzyme-linked immunosorbent assay. The effects of drugs on the degradation of A?42 were studied. Results: A?42 was targeted to detergent-resistant, low-density membranes (lipid rafts), trafficked via a pathway that avoided the lysosomes, and was slowly degraded by neurons (half-life was greater than 5 days). The metabolism of A?42 was sensitive to pharmacological manipulation. In neurons treated with the cholesterol synthesis inhibitor squalestatin, less A?42 was found within rafts, greater amounts of A?42 were found in lysosomes, and the half-life of A?42 was reduced to less than 24 hours. Treatment with phospholipase A2 inhibitors or platelet-activating factor (PAF) antagonists had the same effects on A?42 metabolism in neurons as squalestatin. PAF receptors were concentrated in the endoplasmic reticulum (ER) along with enzymes that constitute the cholesterol ester cycle. The addition of PAF to ER membranes triggered activation of cholesterol ester hydrolases and the release of cholesterol from stores of cholesterol esters. An inhibitor of cholesterol ester hydrolases (diethylumbelliferyl phosphate) also increased the degradation of A?42 in neurons. Conclusions: We conclude that the targeting of A?42 to rafts in normal cells is a factor that affects its degradation. Critically, pharmacological manipulation of neurons can significantly increase A?42 degradation. These results are consistent with the hypothesis that the A?-induced production of PAF controls a cholesterol-sensitive pathway that affects the cellular localization and hence the fate of A?42 in neurons. Twit Text FOAVip Platelet-activating factor antagonists enhance intracellular degradation of amyloid- 42 in neurons via regulation of cholesterol ester hydrolases ????Alzheimers Res Ther http://www.kidney.de/pget.php?&tw=1&pmid=24625058 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24625058 #FOAvip English Wikipedia <ref>{{Cite pmid|24625058}}</ref> Platelet-activating factor antagonists enhance intracellular degradation of amyloid-?42 in neurons via regulation of cholesterol ester hydrolases #MMPMID24625058 Simmons C; Ingham V; Williams A; Bate C Alzheimers Res Ther 2014[]; 6 (2): 15 PMID24625058show ga Introduction: The progressive dementia that is characteristic of Alzheimer?s disease is associated with the accumulation of amyloid-beta (A?) peptides in extracellular plaques and within neurons. A? peptides are targeted to cholesterol-rich membrane micro-domains called lipid rafts. Observations that many raft proteins undertake recycling pathways that avoid the lysosomes suggest that the accumulation of A? in neurons may be related to A? targeting lipid rafts. Here we tested the hypothesis that the degradation of A? by neurons could be increased by drugs affecting raft formation. Methods: Primary neurons were incubated with soluble A? preparations. The amounts of A?42 in neurons or specific cellular compartments were measured by enzyme-linked immunosorbent assay. The effects of drugs on the degradation of A?42 were studied. Results: A?42 was targeted to detergent-resistant, low-density membranes (lipid rafts), trafficked via a pathway that avoided the lysosomes, and was slowly degraded by neurons (half-life was greater than 5 days). The metabolism of A?42 was sensitive to pharmacological manipulation. In neurons treated with the cholesterol synthesis inhibitor squalestatin, less A?42 was found within rafts, greater amounts of A?42 were found in lysosomes, and the half-life of A?42 was reduced to less than 24 hours. Treatment with phospholipase A2 inhibitors or platelet-activating factor (PAF) antagonists had the same effects on A?42 metabolism in neurons as squalestatin. PAF receptors were concentrated in the endoplasmic reticulum (ER) along with enzymes that constitute the cholesterol ester cycle. The addition of PAF to ER membranes triggered activation of cholesterol ester hydrolases and the release of cholesterol from stores of cholesterol esters. An inhibitor of cholesterol ester hydrolases (diethylumbelliferyl phosphate) also increased the degradation of A?42 in neurons. Conclusions: We conclude that the targeting of A?42 to rafts in normal cells is a factor that affects its degradation. Critically, pharmacological manipulation of neurons can significantly increase A?42 degradation. These results are consistent with the hypothesis that the A?-induced production of PAF controls a cholesterol-sensitive pathway that affects the cellular localization and hence the fate of A?42 in neurons. äPlatelet-activating factor antagonists enhance intracellular degradati(epmc).pdf DeepDyve Pubget Overpricing