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.

睡眠不足或碎片化导致的慢性睡眠中断 (CSD) 是阿尔茨海默病 (AD) 的重要危险因素。根本机制尚不清楚。小鼠中的 CSD 导致蓝斑神经元 (LCn) 和 CA1 海马神经元变性，并增加海马淀粉样蛋白-β ₄₂ (Aβ ₄₂ )、内嗅皮层 (EC) tau 磷酸化 (p-tau) 和神经胶质反应性。 LCN 损伤越来越多地与 AD 发病机制相关。 CSD 增加 LCn 中的 NE 周转，并且 LCn 去甲肾上腺素 (NE) 代谢会激活天冬酰胺内肽酶 (AEP)，这种酶已知可将淀粉样前体蛋白 (APP) 和 tau 蛋白裂解成神经毒性片段。我们假设 CSD 会以 NE 依赖性方式激活 LCn AEP，从而诱导 LCn 和海马损伤。在这里，我们使用慢性碎片化睡眠 (CFS) 模型，研究了 NE [多巴胺 β-羟化酶 ( Dbh ) ^–/– ] 缺陷小鼠和对照雄性和雌性小鼠的 LCn、海马和 EC 对 CSD 的反应。 Dbh ^–/–以及对照雄性和雌性小鼠的睡眠同样不完整，但只有Dbh ^–/–小鼠对 CFS LCn、LCn p-tau 和 LCn AEP 上调和激活的损失具有抵抗力，如 AEP- 增加所证明的那样。切割 APP 和 tau 片段。缺乏 NE 还可以阻止海马 AEP-APP 和 Aβ ₄₂的 CFS 增加，但不能阻止 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 CFS LCn 神经元变性和 CFS 促进前脑 Aβ 积累中的关键作用，从而确定了 CSD 和特定 AD 神经损伤之间的关键分子联系。