PDF(Pubmed)
Abstract：
Treatments for Alzheimer\'s disease have primarily focused on removing brain amyloid plaques to improve cognitive outcomes in patients. We developed small compounds, known as BK40143 and BK40197, and we hypothesize that these drugs alleviate microglial-mediated neuroinflammation and induce autophagic clearance of neurotoxic proteins to improve behavior in models of neurodegeneration. Specificity binding assays of BK40143 and BK40197 showed primary binding to c-KIT/Platelet Derived Growth Factor Receptors (PDGFR)α/β, whereas BK40197 also differentially binds to FYVE finger-containing phosphoinositide kinase (PIKFYVE). Both compounds penetrate the CNS, and treatment with these drugs inhibited the maturation of peripheral mast cells in transgenic mice, correlating with cognitive improvements on measures of memory and anxiety. In the brain, microglial activation was profoundly attenuated and amyloid-beta and tau were reduced via autophagy. Multi-kinase inhibition, including c-KIT, exerts multifunctional effects to reduce neurodegenerative pathology via autophagy and microglial activity and may represent a potential therapeutic option for neurodegeneration.
摘要：
阿尔茨海默病的治疗主要集中在去除脑淀粉样蛋白斑块以改善患者的认知结果。我们开发了小化合物,被称为BK40143和BK40197，我们假设这些药物可以减轻小胶质细胞介导的神经炎症，并诱导神经毒性蛋白的自噬清除，从而改善神经变性模型的行为。BK40143和BK40197的特异性结合测定显示与c-KIT/血小板衍生生长因子受体（PDGFR）α/β，而BK40197也差异结合FYVE含指状磷酸肌醇激酶(PIKFYVE)。这两种化合物都能穿透中枢神经系统,这些药物的治疗抑制了转基因小鼠外周肥大细胞的成熟，与记忆和焦虑的认知改善相关。在大脑中,通过自噬,小胶质细胞的激活明显减弱,β-淀粉样蛋白和tau蛋白降低.多激酶抑制，包括c-KIT,通过自噬和小胶质细胞活性发挥多功能作用以减少神经退行性病变，并且可能代表神经退行性病变的潜在治疗选择。
