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10.1074/jbc.M116.754101 http://scihub22266oqcxt.onion/10.1074/jbc.M116.754101 C5339758!5339758!28096459     free     free     free Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 243.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       J+Biol+Chem 2017 ; 292 (9): 3751-67 Nephropedia Template TP {{tp|p=28096459|t=2017. Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by ?-Secretase and Amyloid-? Peptide Production* |pdf=|usr=}}{{28096459}} gab.com Text Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by -Secretase and Amyloid- Peptide Production* JO: J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=28096459 #FOAvip Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-? peptide (A?). However, little is known about whether these biometals modulate the generation of A?. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate A? production by distinct molecular mechanisms affecting the processing by ?-secretase of its A? precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by ?-secretase and A? production, with an IC50 value of 15 ?m. Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone A?43 found in the senile plaques of AD brains and elevated the A?43:A?40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of A? production, whereas the increased A?43:A?40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited A? production by directly targeting the subunits presenilin and nicastrin in the ?-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate A? production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic A? species, may offer two therapeutic strategies for preventing AD. Twit Text FOAVip Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by -Secretase and Amyloid- Peptide Production* ????J Biol Chem http://www.kidney.de/pget.php?&tw=1&pmid=28096459 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28096459 #FOAvip English Wikipedia <ref>{{Cite pmid|28096459}}</ref> Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by ?-Secretase and Amyloid-? Peptide Production* #MMPMID28096459 Gerber H; Wu F; Dimitrov M; Garcia Osuna GM; Fraering PC J Biol Chem 2017[Mar]; 292 (9): 3751-67 PMID28096459show ga Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-? peptide (A?). However, little is known about whether these biometals modulate the generation of A?. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate A? production by distinct molecular mechanisms affecting the processing by ?-secretase of its A? precursor protein substrate APP-C99. We found that Zn2+ induces APP-C99 dimerization, which prevents its cleavage by ?-secretase and A? production, with an IC50 value of 15 ?m. Importantly, at this concentration, Zn2+ also drastically raised the production of the aggregation-prone A?43 found in the senile plaques of AD brains and elevated the A?43:A?40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn2+-dependent APP-C99 dimerization and inhibition of A? production, whereas the increased A?43:A?40 ratio is substrate dimerization-independent and involves the known Zn2+ binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited A? production by directly targeting the subunits presenilin and nicastrin in the ?-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate A? production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic A? species, may offer two therapeutic strategies for preventing AD. äZinc and Copper Differentially Modulate Amyloid Precursor Protein Proc(epmc).pdf DeepDyve Pubget Overpricing