Norepinephrine: A Novel Regulator of Amyloid Beta-42 Peptides

项目总结： 来自临床和临床前研究的一致证据强调了异常的有害影响。 淀粉样β蛋白(Aβ42)多肽的积聚，从神经元功能障碍到行为和心理 疾病的表现。来自最近临床研究的令人信服的证据表明，Aβ42水平升高 在中老年非痴呆成年人中，多肽与焦虑和抑郁症状有关，因为 以及轻度认知障碍(MCI)或阿尔茨海默病(AD)早期患者。压力是一种风险 精神疾病以及发展成阿尔茨海默病的因素。此外，已经证明，扩增 应激系统破坏突触的细胞和分子过程，促进细胞和 Aβ-42多肽的分泌。去甲肾上腺素(NE)-蓝斑(LC)系统是应激反应系统 神经回路与应激相关的精神障碍，以及AD的病因和进展有关。数不胜数 文献中的研究支持去甲肾上腺素作为Aβ42肽水平的调节器的作用，因为存在细胞机制 NE可通过此途径影响A-β-42多肽的产生和降解清除。然而， 在NE如何调节Aβ42肽水平的知识上存在着显著的差距。早期的调节失调 NE系统被认为是痴呆症(BPSD)的行为和精神症状的基础，通常 在MCI患者中观察到的第一个症状后来发展为AD。因为NE可以产生深远的影响 慢性应激条件下A-β-42多肽的产生和清除、去甲肾上腺素的异常调节 精神疾病或LC变性可能直接导致Aβ42肽的异常积聚。因此， 靶向LC-NE系统可能是在早期阶段调节Aβ42水平以减缓或阻止 疾病的发展。拟议的研究旨在研究去甲肾上腺素在调节淀粉样βAβ42中的作用 多肽水平。我们将在我们最近发表的工作的基础上，展示Aβ42肽对LC的解剖定位 幼年雄性和雌性大鼠内侧前额叶的躯体树突和去甲肾上腺素能轴突终末 大脑皮层(MPFC)，一个重要的应激反应整合区域和LC的主要投射部位 神经元。我们还研究了NE耗竭对Aβ42肽的影响，方法是对NE的DβH进行基因缺失 合成酶。结果表明，NE耗竭显著降低了Aβ42肽的水平 用ELISA法。此外，在一个利用增加的兴奋性输入来增强LC活动的模型中，模拟慢性 应激时，Aβ42在LC的躯体树突中的定位增加。这些数据已经告诉我们 我们目前的方法研究在DβH基因敲除中应用LDOPS后Aβ42水平的动态调节 在DβH-Cre x牙线状ADRA2A型小鼠中，这是一种更直接的NE传播增加的模型。无论是男性还是 将对女性进行检查，以探索去甲肾上腺素对Aβ42肽水平作用机制的潜在性别差异。

Project Summary: Convergent evidence from clinical and preclinical studies have highlighted the deleterious effects of aberrant accumulation of the amyloid beta (Aβ42) peptide, from neuronal dysfunction to behavioral and psychological manifestations of disease. Compelling evidence from recent clinical studies reveal that elevated levels of Aβ42 peptides are associated with anxiety and depression symptoms in middle-aged and older non-demented adults, as well as those with mild cognitive impairment (MCI) or in early stages of Alzheimer's disease (AD). Stress is a risk factor for psychiatric disease, as well as for developing AD. Further, it has been demonstrated that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and secretion of Aβ42 peptides. The norepinephrine (NE)- locus coeruleus (LC) system is a stress-responsive neurocircuit implicated in stress-related psychiatric disorders, and in the etiology and progression of AD. Numerous studies in the literature support a role for NE as a regulator of Aβ42 peptide levels, as there are cellular mechanisms by which NE can influence both the production and the degradation and clearance of Aβ42 peptides. However, there exist significant gaps in knowledge regarding how NE regulates Aβ42 peptide levels. Early dysregulation of the NE system is thought to underlie the behavioral and psychiatric symptoms of dementia (BPSD), which are often the first symptoms observed in MCI patients that later progress to AD. Because NE can exert profound effects on the production and clearance of Aβ42 peptides, the dysregulation of NE under conditions of chronic stress, psychiatric disease, or LC degeneration may directly contribute to aberrant accumulation of Aβ42 peptides. Thus, targeting the LC-NE system may be a novel avenue to modulate Aβ42 levels in early stages to slow or halt the progression of disease. The proposed studies aim to investigate the role of NE in regulating amyloid beta Aβ42 peptide levels. We will build on our recent published work showing anatomical localization of Aβ42 peptides to LC somatodendritic processes and to noradrenergic axon terminals of the naïve male and female rat medial prefrontal cortex (mPFC), a region important for the integration of the stress response and a major projection site of LC neurons. We also examined consequences of NE depletion on Aβ42 peptides using genetic deletion of DβH, the NE synthesizing enzyme. Results showed that NE depletion significantly decreased levels of Aβ42 peptides as measured by ELISA. Moreover, in a model that utilizes increased excitatory input to augment LC activity, simulating chronic stress, there is increased localization of Aβ42 to somatodendritic processes of the LC. These data have informed our current approach to examine dynamic regulation of Aβ42 levels following LDOPS administration in DβH knockout mice and in DβH-CRE x floxed Adra2a mice, a more direct model of increased NE transmission. Both males and females will be examined to probe for potential sex differences in mechanism of action of NE on Aβ42 peptide levels.