RESUMO
Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Encéfalo/metabolismo , Endopeptidases/metabolismo , Secretases da Proteína Precursora do Amiloide , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Ácido Aspártico Endopeptidases , Celecoxib , Linhagem Celular , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Fenofibrato/química , Fenofibrato/farmacologia , Humanos , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular , Espectrometria de Massas , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Transfecção , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels.