AC Immune SA, Lausanne, Switzerland.
J Alzheimers Dis. 2014;38(4):767-86. doi: 10.3233/JAD-131091.
The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects.
有毒淀粉样β肽（Aβ）在大脑中的形成和积累可能会导致阿尔茨海默病的发病机制。因此，调节 Aβ动态平衡的治疗方法可能会产生用于治疗阿尔茨海默病和相关疾病的疗法。这些方法包括抑制 Aβ的产生、错误折叠和积累，或增强其清除。在这里，我们表明，在 AβPPPS1、hAβPPSL 和 AβPP/PS1 转基因小鼠中，ACI-91（哌仑西平）的口服治疗剂量依赖性地降低了大脑中的 Aβ负担。ACI-91 的可能作用机制可能是通过选择性抑制脑微血管内皮细胞上的毒蕈碱乙酰胆碱受体（AChR）并增强 Aβ 肽穿过血脑屏障的清除。用 ACI-91 治疗一个月可增加在斑块携带小鼠中鞘内注射的 Aβ的清除率。ACI-91 还通过促进其尿排泄来加速脑内注射 Aβ在血液和外周组织中的清除。ACI-91 的单次口服剂量可降低预斑块 mhAβPP/PS1d 小鼠中间质 Aβ 肽的半衰期。通过将我们的研究扩展到体外模型，我们表明 ACI-91 和 Darifenacin 对毒蕈碱 AChR 的抑制作用增强了分化的内皮单层对 Aβ 肽主动转运的能力。最后，发现 ACI-91 一致地影响体外和体内涉及 Aβ穿过血脑屏障（BBB）的内皮细胞基因的表达。因此，通过 BBB 增加 Aβ清除可能有助于降低 Aβ负担和相关表型。局限于外周的毒蕈碱乙酰胆碱受体的抑制可能具有治疗优势，因为它避免了中枢胆碱能的不良反应。
