PDF(Pubmed)
Abstract：
Chronic sleep disruption (CSD), from insufficient or fragmented sleep and is an important risk factor for Alzheimer\'s disease (AD). Underlying mechanisms are not understood. CSD in mice results in degeneration of locus ceruleus neurons (LCn) and CA1 hippocampal neurons and increases hippocampal amyloid-β42 (Aβ42), entorhinal cortex (EC) tau phosphorylation (p-tau), and glial reactivity. LCn injury is increasingly implicated in AD pathogenesis. CSD increases NE turnover in LCn, and LCn norepinephrine (NE) metabolism activates asparagine endopeptidase (AEP), an enzyme known to cleave amyloid precursor protein (APP) and tau into neurotoxic fragments. We hypothesized that CSD would activate LCn AEP in an NE-dependent manner to induce LCn and hippocampal injury. Here, we studied LCn, hippocampal, and EC responses to CSD in mice deficient in NE [dopamine β-hydroxylase (Dbh)-/-] and control male and female mice, using a model of chronic fragmentation of sleep (CFS). Sleep was equally fragmented in Dbh -/- and control male and female mice, yet only Dbh -/- mice conferred resistance to CFS loss of LCn, LCn p-tau, and LCn AEP upregulation and activation as evidenced by an increase in AEP-cleaved APP and tau fragments. Absence of NE also prevented a CFS increase in hippocampal AEP-APP and Aβ42 but did not prevent CFS-increased AEP-tau and p-tau in the EC. Collectively, this work demonstrates AEP activation by CFS, establishes key roles for NE in both CFS degeneration of LCn neurons and CFS promotion of forebrain Aβ accumulation, and, thereby, identifies a key molecular link between CSD and specific AD neural injuries.
摘要：
慢性睡眠中断（CSD）由于睡眠不足或零散，是阿尔茨海默病(AD)的重要危险因素。潜在机制，然而,不理解。小鼠的CSD导致蓝斑神经元（LCn）和CA1海马神经元变性，并增加海马淀粉样β42（Aβ42），内嗅皮层（EC）tau磷酸化（p-tau）和神经胶质反应性。LCn损伤越来越多地参与AD的发病机制。CSD增加了LCn的NE营业额，和LCN去甲肾上腺素（NE）代谢激活天冬酰胺内肽酶（AEP），一种已知将淀粉样蛋白前体蛋白（APP）和tau切割成神经毒性片段的酶。我们假设CSD会以NE依赖性方式激活LCnAEP，以诱导LCn和海马损伤。这里,我们研究了LCN,缺乏NE（多巴胺β-羟化酶（Dbh）-/-）的小鼠和对照雄性和雌性小鼠对CSD的海马和EC反应，使用慢性睡眠破碎（CFS）模型。Dbh-/-和对照雄性和雌性小鼠的睡眠同样破碎，然而，只有Dbh-/-小鼠对LCn的CFS丧失具有抗性，LCNp-tau,和LCnAEP上调和激活,如通过AEP切割的APP和tau片段的增加所证明的。缺乏NE也可以防止海马AEP-APP和Aβ42的CFS增加，但不能防止EC中CFS增加的AEP-tau和p-tau。总的来说，这项工作证明了CFS激活AEP，确立了NE在LCn神经元的CFS变性和CFS促进前脑Aβ积累中的关键作用，因此，确定CSD和特定AD神经损伤之间的关键分子联系。睡眠中断通常发生并增加AD的风险，然而，分子机制尚不清楚。LCn为大部分大脑提供NE，其中NE主要具有神经保护作用。然而,LCn中NE的代谢可促进与AD神经损伤有关的致病性淀粉样蛋白和tau片段的形成。这里,我们发现睡眠中断增加了LCn中有毒淀粉样蛋白和tau片段的形成，而NE驱动了这些片段的形成，LCn丢失和海马淀粉样β积累。这项工作确定了与迟发性或自发性AD有关的睡眠损失神经损伤的分子窗口。
