RESUMEN
The death of cholinergic neurons in the cerebral cortex and certain subcortical regions is linked to irreversible dementia relevant to AD (Alzheimer's disease). Although multiple studies have shown that expression of a FAD (familial AD)-linked APP (amyloid ß precursor protein) or a PS (presenilin) mutant, but not that of wild-type APP or PS, induced neuronal death by activating intracellular death signals, it remains to be addressed how these signals are interrelated and what the key molecule involved in this process is. In the present study, we show that the PS1-mediated (or possibly the PS2-mediated) signal is essential for the APP-mediated death in a γ-secretase-independent manner and vice versa. MOCA (modifier of cell adhesion), which was originally identified as being a PS- and Rac1-binding protein, is a common downstream constituent of these neuronal death signals. Detailed molecular analysis indicates that MOCA is a key molecule of the AD-relevant neuronal death signals that links the PS-mediated death signal with the APP-mediated death signal at a point between Rac1 [or Cdc42 (cell division cycle 42)] and ASK1 (apoptosis signal-regulating kinase 1).
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Portadoras/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Presenilinas/genética , Presenilinas/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Animales , Secuencia de Bases , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Muerte Celular , Cartilla de ADN/genética , Técnicas de Silenciamiento del Gen , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Células Híbridas , MAP Quinasa Quinasa Quinasa 5/metabolismo , Ratones , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Neuronas/patología , Neuropéptidos , Presenilinas/antagonistas & inhibidores , ARN Interferente Pequeño/genética , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , Proteínas de Unión al GTP rac , Proteína de Unión al GTP rac1RESUMEN
Our earlier studies indicated that TGFbeta2-induced neuronal cell death by binding to the extracellular domain of amyloid beta precursor protein (APP) on the cell surface and by triggering an intracellular death signal pathway, mediated by a heterotrimeric G protein Go, Rac1/cdc42, ASK1, JNK, NADPH oxidase, and caspases in this order. Recently, transient axonal glycoprotein-1 (TAG-1), a glycophosphatidylinositol-linked protein, was identified as another natural ligand of APP. TAG-1 increases APP intracellular domain release and triggers FE65-dependent transcriptional activity in a gamma-secretase-dependent manner by binding to APP. In this study, we show that TAG-1 inhibits TGFbeta2-mediated neuronal cell death via APP by attenuating the binding of TGFbeta2 to APP in a gamma-secretase-independent manner. TAG-1 is expressed in murine hippocampal neurons at 8 weeks of age, but its expression is reduced at 8 and 20 months. These findings suggest that an age-related reduction of TAG-1 expression may predispose neurons to cell death, induced by the binding of TGFbeta2 to APP. This mechanism may contribute to the onset and the progression of Alzheimer's disease-relevant neuronal cell death.