Publication Date:
2003-11-15
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yan -- Su, Yuan -- Li, Baolin -- Liu, Feng -- Ryder, John W -- Wu, Xin -- Gonzalez-DeWhitt, Patricia A -- Gelfanova, Valentina -- Hale, John E -- May, Patrick C -- Paul, Steven M -- Ni, Binhui -- New York, N.Y. -- Science. 2003 Nov 14;302(5648):1215-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. zhou_yan_yz@lilly.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14615541" target="_blank"〉PubMed〈/a〉
Keywords:
Amides/pharmacology
;
Amyloid Precursor Protein Secretases
;
Amyloid beta-Peptides/*metabolism
;
Animals
;
Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
;
Aspartic Acid Endopeptidases
;
Brain/drug effects/metabolism
;
Cell Line, Tumor
;
Endopeptidases/metabolism
;
Enzyme Inhibitors/pharmacology
;
Guanosine Triphosphate/metabolism
;
Humans
;
Ibuprofen/pharmacology
;
Intracellular Signaling Peptides and Proteins
;
Mice
;
Mice, Transgenic
;
Peptide Fragments/*metabolism
;
Polyisoprenyl Phosphates/pharmacology
;
Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
;
Pyridines/pharmacology
;
Sesquiterpenes
;
Signal Transduction
;
Sulindac/*analogs & derivatives/pharmacology
;
Transfection
;
rho GTP-Binding Proteins/*antagonists & inhibitors/metabolism
;
rho-Associated Kinases
;
rhoA GTP-Binding Protein/genetics/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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