昼夜节律紊乱上调ET-1/DAG/PKC通路促进β-淀粉样蛋白沉积的机制

基于早期可逆性危险因素的机制研究对预防阿尔茨海默病（AD）至关重要。昼夜节律紊乱可促进AD的进展及其病理特征β-淀粉样蛋白（Aβ）的病理性沉积。但昼夜节律紊乱促进Aβ沉积的机制尚不明确。申请人先前研究证实脑微血管损伤是AD的危险因素，其可能的重要通路ET-1/DAG/PKC受到昼夜节律调节。我们在预实验中发现AD患者DAG水平升高，并且注射外源性ET-1加速了AD转基因小鼠的Aβ沉积。因此我们提出“昼夜节律紊乱通过上调ET-1/DAG/PKC通路促进Aβ沉积”的假说。本研究拟：①通过动物实验，证实在光暗周期紊乱条件下AD转基因小鼠ET-1/DAG/PKC通路上调促进了Aβ沉积和记忆损害；②通过细胞实验进一步明确脑微血管重要组成部分周皮细胞的ET-1/DAG/PKC通路上调促进Aβ沉积的具体机制。本研究有望为阿尔茨海默病的早期预防和干预提供新的手段。

It is critically important to identify the reversible risk factor for the prevention and intervention of Alzheimer’s disease (AD). Circadian rhythm disruption accelerates AD progression and accumulation of β-amyloid protein (Aβ, the pivotal pathology of AD). However, the underlying mechanism is still unclear. Our previous research observed that cerebral microvascular lesions served as important risk factors of AD. The molecular pathway of microvascular injury ET-1/DAG/PKC is regulated by circadian rhythm. In the pilot study, we found the elevation of ET-1/DAG/PKC in AD patients and mouse model. Thus, we hypothesized that the role of circadian rhythm disruption on the Aβ accumulation is mediated by the upregulation of ET-1/DAG/PKC. We will employ ① AD transgenic mice under environmentally disrupted dark/light cycle to testify whether the upregulation of ET-1/DAG/PKC accelerates Aβ accumulation and memory deficits; ② Cell experiments to further clarify whether ET-1/DAG/PKC upregulation in pericytes (key component of cerebral microvessel) accelerates Aβ accumulation. The completion of this study will pave a way for the development of early intervention and preventive strategies for AD.