Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, AB T6G 2MB, Canada.
Molecules. 2021 Dec 18;26(24):7669. doi: 10.3390/molecules26247669.
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 (Aβ) 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 Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ 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.
阿尔茨海默病（AD）是全球最常见的痴呆症病因。尽管针对疾病的主要分子成分——β-淀粉样蛋白（Aβ）和 tau 进行了广泛的研究和靶向治疗，但目前尚无能够改变疾病进展的治疗方法。在这里，我们使用原代培养的小鼠皮质神经元研究了两种特定的钙/钙调蛋白依赖性蛋白激酶 1D（CaMK1D）激酶抑制剂对 Aβ介导的毒性的影响。tau 过度磷酸化和细胞死亡被用作 AD 的指标。这些特定的抑制剂被发现可以预防培养物中 Aβ诱导的 tau 过度磷酸化，但不能保护细胞免受 Aβ诱导的毒性。虽然抑制剂能够改变细胞培养物中的 AD 病理，但不足以防止细胞死亡。随着进一步的研究和开发，这些抑制剂可能有助于开发一种多药物策略来对抗 AD。
