Norepinephrine: A Novel Regulator of Amyloid Beta-42 Peptides

项目摘要： 来自临床和临床前研究的一致证据已经强调了异常免疫抑制剂的有害影响。 淀粉样β（Aβ42）肽的积累，从神经元功能障碍到行为和心理 疾病的表现。近期临床研究的有力证据表明，Aβ42水平升高 肽与中年和老年非痴呆成年人的焦虑和抑郁症状有关， 以及轻度认知障碍（MCI）或阿尔茨海默病（AD）早期的患者。压力是一种风险 精神疾病的因素，以及发展AD。此外，已经证明，放大 压力系统的破坏在突触的细胞和分子过程，促进生产和 Aβ42肽的分泌。去甲肾上腺素（NE）-蓝斑（LC）系统是一个应激反应性的神经元系统。 神经回路参与应激相关的精神障碍，并在AD的病因和进展。许多 文献中的研究支持NE作为Aβ42肽水平调节剂的作用，因为存在细胞机制 NE可通过此途径影响Aβ42肽的产生、降解和清除。然而，在这方面， 关于NE如何调节Aβ42肽水平的知识存在重大空白。早期调节失调 NE系统被认为是痴呆的行为和精神症状（BPSD）的基础，这些症状通常是 在MCI患者中观察到的最初症状，随后进展为AD。因为NE可以发挥深远的影响， Aβ42肽的产生和清除，慢性应激条件下NE的失调， 精神疾病或LC变性可能直接导致Aβ42肽异常蓄积。因此，在本发明中， 靶向LC-NE系统可能是在早期调节Aβ42水平以减缓或停止 疾病的进展。这些研究旨在探讨NE在调节淀粉样β Aβ42中的作用。 肽水平。我们将建立在我们最近发表的工作，显示解剖定位Aβ42肽LC 幼年雄性和雌性大鼠内侧前额叶的体突和去甲肾上腺素能轴突终末 皮质（mPFC），一个重要的区域整合的压力反应和一个主要的投影网站的LC 神经元我们还使用DβH基因缺失，NE缺失对Aβ42肽的影响， 合成酶结果显示，NE消耗显着降低了Aβ42肽的水平 采用ELISA此外，在利用增加的兴奋性输入来增强LC活性的模型中，模拟慢性炎症。 应激时，Aβ42在LC体树突突起的定位增加。这些数据告诉 我们目前的方法是在DβH基因敲除的小鼠中检测LDOPS给药后Aβ42水平的动态调节 小鼠和DβH-CRE x floxed Adra 2a小鼠中，NE传递增加的更直接模型。男性和 将对雌性动物进行检查，以探索NE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.