Shanghai Institute of Materia Medica-University of Ottawa Joint Research Centre on Systems and Personalized Pharmacology , University of Ottawa , Ottawa , ON K1H 8M5 , Canada.
Ottawa Institute of Systems Biology and Department of Biochemistry, Microbiology and Immunology , University of Ottawa , Ottawa , ON K1H 8M5 , Canada.
J Proteome Res. 2019 Sep 6;18(9):3383-3393. doi: 10.1021/acs.jproteome.9b00312. Epub 2019 Aug 6.
Sleep disturbances and memory impairment are common symptoms of Alzheimer's disease (AD). Given that the circadian clock regulates sleep, hippocampal function, and neurodegeneration, it represents a therapeutic target against AD. Casein kinase 1δ/ε (CK1δ/ε) are clock regulators and overexpressed in AD brains, making them viable targets to improve sleep and cognition. In this study, we evaluated the therapeutic potential of a small molecule CK1δ/ε inhibitor (PF-670462) in a triple transgenic mouse model of AD (3xTg-AD). Mass spectrometry-based proteomic analyses revealed that PF-670462 administration in 3xTg-AD mice reversed hippocampal proteomic alterations in several AD-related and clock-regulated pathways, including synaptic plasticity and amyloid precursor protein processing. Furthermore, PF-670462 administration rescued working memory deficits and normalized behavioral circadian rhythm disturbances in 3xTg-AD mice. Our study provides in vivo proof of concept for CK1δ/ε inhibition against AD-associated hippocampal proteomic changes, memory impairment, and circadian disturbances.
睡眠障碍和记忆损伤是阿尔茨海默病（AD）的常见症状。鉴于生物钟调节睡眠、海马功能和神经退行性变，它是治疗 AD 的一个有前途的靶点。酪蛋白激酶 1δ/ε（CK1δ/ε）是生物钟调节剂，在 AD 大脑中过度表达，使其成为改善睡眠和认知的可行靶点。在这项研究中，我们评估了小分子 CK1δ/ε 抑制剂（PF-670462）在三转基因 AD 小鼠模型（3xTg-AD）中的治疗潜力。基于质谱的蛋白质组学分析显示，PF-670462 给药可逆转 3xTg-AD 小鼠海马中几种与 AD 相关和生物钟调节的途径中的蛋白质组改变，包括突触可塑性和淀粉样前体蛋白加工。此外，PF-670462 给药可改善 3xTg-AD 小鼠的工作记忆缺陷，并使行为昼夜节律紊乱正常化。我们的研究为 CK1δ/ε 抑制对抗 AD 相关的海马蛋白质组变化、记忆损伤和昼夜节律紊乱提供了体内概念验证。
