神经退行性变
昼夜节律
海马结构
神经科学
转基因小鼠
酪蛋白激酶1
阿尔茨海默病
突触可塑性
淀粉样前体蛋白
转基因
海马体
生物钟
生物
医学
疾病
激酶
内科学
蛋白激酶A
细胞生物学
生物化学
受体
基因
作者
Paula Adler,Janice Mayne,Krystal Walker,Zhibin Ning,Daniel Figeys
标识
DOI:10.1021/acs.jproteome.9b00312
摘要
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.
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