RESUMEN
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aß) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aß-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aß induced tau hyperphosphorylation in culture, but were not able to protect cells from Aß induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Modelos Animales de Enfermedad , Neuronas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Neuronas/metabolismo , Neuronas/patología , Inhibidores de Proteínas Quinasas/químicaRESUMEN
Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective, and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.