Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Nanjing, People's Republic of China.
PLoS One. 2011 Jan 28;6(1):e16037. doi: 10.1371/journal.pone.0016037.
Stress and various stress hormones, including catecholamines and glucocorticoids, have recently been implicated in the pathogenesis of Alzheimer's disease (AD), which represents the greatest unresolved medical challenge in neurology. Angiotensin receptor blockers have shown benefits in AD and prone-to-AD animals. However, the mechanisms responsible for their efficacy remain unknown, and no studies have directly addressed the role of central angiotensin II (Ang II), a fundamental stress hormone, in the pathogenesis of AD. The present study focused on the role of central Ang II in amyloidogenesis, the critical process in AD neuropathology, and aimed to provide direct evidence for the role of this stress hormone in the pathogenesis of AD.
METHODOLOGY/PRINCIPAL FINDINGS: Increased central Ang II levels during stress response were modeled by intracerebroventricular (ICV) administration of graded doses of Ang II (6 ng/hr low dose, 60 ng/hr medium dose, and 600 ng/hr high dose, all delivered at a rate of 0.25 µl/hr) to male Sprague Dawley rats (280-310 g) via osmotic pumps. After 1 week of continuous Ang II infusion, the stimulation of Ang II type 1 receptors was accompanied by the modulation of amyloid precursor protein, α-, β-and γ-secretase, and increased β amyloid production. These effects could be completely abolished by concomitant ICV infusion of losartan, indicating that central Ang II played a causative role in these alterations.
CONCLUSIONS/SIGNIFICANCE: Central Ang II is essential to the stress response, and the results of this study suggest that increased central Ang II levels play an important role in amyloidogenesis during stress, and that central Ang II-directed stress prevention and treatment might represent a novel anti-AD strategy.
压力和各种应激激素，包括儿茶酚胺和糖皮质激素，最近被牵连到阿尔茨海默病（AD）的发病机制中，这是神经病学中最大的未解决的医学挑战。血管紧张素受体阻滞剂在 AD 和易患 AD 的动物中显示出益处。然而，其疗效的机制尚不清楚，也没有研究直接解决中枢血管紧张素 II（Ang II）在 AD 发病机制中的作用，Ang II 是一种基本的应激激素。本研究侧重于中枢 Ang II 在淀粉样蛋白形成中的作用，淀粉样蛋白形成是 AD 神经病理学的关键过程，并旨在为该应激激素在 AD 发病机制中的作用提供直接证据。
方法/主要发现：通过颅内（ICV）给予不同剂量的 Ang II（低剂量 6ng/hr，中剂量 60ng/hr，高剂量 600ng/hr，均以 0.25µl/hr 的速度给药）来模拟应激反应期间中枢 Ang II 水平的升高，该方法向雄性 Sprague Dawley 大鼠（280-310g）通过渗透泵给药。在持续 Ang II 输注 1 周后，Ang II 型 1 受体的刺激伴随着淀粉样前体蛋白、α-、β-和 γ-分泌酶的调节以及β淀粉样蛋白生成的增加。这些作用可以通过同时给予 losartan 完全消除，表明中枢 Ang II 在这些改变中起因果作用。
结论/意义：中枢 Ang II 对应激反应至关重要，本研究结果表明，应激期间中枢 Ang II 水平的升高在淀粉样蛋白形成中起重要作用，中枢 Ang II 定向的应激预防和治疗可能代表一种新的抗 AD 策略。
