title: Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho.
abstract: A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.
authors: Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhou_yan_yz@lilly.com
authors: Yan
authors: Y
authors: Zhou
authors: Yuan
authors: Y
authors: Su
authors: Baolin
authors: B
authors: Li
authors: Feng
authors: F
authors: Liu
authors: John W
authors: JW
authors: Ryder
authors: Xin
authors: X
authors: Wu
authors: Patricia A
authors: PA
authors: Gonzalez-DeWhitt
authors: Valentina
authors: V
authors: Gelfanova
authors: John E
authors: JE
authors: Hale
authors: Patrick C
authors: PC
authors: May
authors: Steven M
authors: SM
authors: Paul
authors: Binhui
authors: B
authors: Ni
mesh_terms: D000577:Amides / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012717:Sesquiterpenes; D015398:Signal Transduction; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012717:Sesquiterpenes; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); C108830:Y 27632; D013467:Sulindac; C025462:sulindac sulfide; C004808:farnesyl pyrophosphate; D006160:Guanosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C002963:geranylgeranyl pyrophosphate; D007052:Ibuprofen