RESUMO
Recent studies demonstrated that the antihypertensive drug Valsartan improved spatial and episodic memory in mouse models of Alzheimer's Disease (AD) and human subjects with hypertension. However, the molecular mechanism by which Valsartan can regulate cognitive function is still unknown. Here, we investigated the effect of Valsartan on dendritic spine formation in primary hippocampal neurons, which is correlated with learning and memory. Interestingly, we found that Valsartan promotes spinogenesis in developing and mature neurons. In addition, we found that Valsartan increases the puncta number of PSD-95 and trends toward an increase in the puncta number of synaptophysin. Moreover, Valsartan increased the cell surface levels of AMPA receptors and selectively altered the levels of spinogenesis-related proteins, including CaMKIIα and phospho-CDK5. These data suggest that Valsartan may promote spinogenesis by enhancing AMPA receptor trafficking and synaptic plasticity signaling.
Assuntos
Anti-Hipertensivos/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Receptores de AMPA/metabolismo , Tetrazóis/farmacologia , Valina/análogos & derivados , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Fosforilação , Transporte Proteico , Ratos , Ratos Wistar , Sinaptofisina/metabolismo , Valina/farmacologia , ValsartanaRESUMO
The cytoplasmic C-terminus of APP plays critical roles in its cellular trafficking and delivery to proteases. Adaptor proteins with phosphotyrosine-binding (PTB) domains, including those in the X11, Fe65, and c-Jun N-terminal kinase (JNK)-interacting protein (JIP) families, bind specifically to the absolutely conserved -YENPTY- motif in the APP C-terminus to regulate its trafficking and processing. Compounds that modulate APP-adaptor protein interactions may inhibit Abeta generation by specifically targeting the substrate (APP) instead of the enzyme (beta- or gamma-secretase). Genetic polymorphisms in (or near) adaptor proteins may influence risk of sporadic AD by interacting with APP in vivo to modulate its trafficking and processing to Abeta.