Rapid β-Amyloid Deposition and Cognitive Impairment After Cholinergic Denervation in APP/PS1 Mice
Rapid β-Amyloid Deposition and Cognitive Impairment After Cholinergic Denervation in APP/PS1 Mice
复制标题
DOI：
10.1097/nen.0b013e318288a8dd
复制
发表时间：
2013-04-01
影响因子：
3.2
通讯作者：
Garcia-Alloza, Monica
中科院分区：
文献类型：
--
作者：
Jose Ramos-Rodriguez, Juan;Pacheco-Herrero, Mar;Garcia-Alloza, Monica
尽管大量证据支持 β-淀粉样蛋白 (Aβ) 在阿尔茨海默病 (AD) 中的作用，但 AD 发病机制背后的神经毒性机制尚不清楚。另一方面，神经元损失是与认知障碍最相关的病理特征。我们假设胆碱能神经变性可能导致 Aβ 沉积，并通过用鼠 p75(NTR) 肥皂草素 (mu p75-SAP) 在 APPswe/PS1dE9 小鼠中诱导选择性胆碱能损伤来测试这一点。在具有初期（类似于 3 个月大）和显着（类似于 7 个月大）A β 沉积的动物中诱导脑室内病变，去除了皮质和海马约 50% 的胆碱能神经支配。植入颅窗，并使用多光子显微镜在体内监测 Aβ 沉积。 Aβ的沉积在病变后7天就增加，并且这种效果一直维持到3个月后。使用抗 Aβ 抗体的免疫组织化学进行的尸检研究证实了大脑皮层和海马体中的这些发现。损伤后Tau磷酸化也显着增加。去胆碱能神经导致 3 个月大时出现早期记忆障碍，并随着年龄的增长而恶化（与 7 个月大时相似）；胆碱能去神经支配和 APP/PS1 转基因的存在之间存在协同效应。总而言之，我们的数据表明，胆碱能去神经可能会引发 Aβ 沉积，并协同导致 AD 患者的认知障碍。
Although extensive evidence supports the role of beta-amyloid (A beta) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathologic feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to A beta deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75(NTR) saporin (mu p75-SAP). Intracerebroventricular lesions that removed approximately 50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (similar to 3 months) and marked (similar to 7 months of age) A beta deposition. Cranial windows were implanted, and A beta deposition was monitored in vivo using multiphoton microscopy. Deposition of A beta was increased as soon as 7 days after the lesion, and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-A beta antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (similar to 7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger A beta deposition and synergistically contribute to cognitive impairment in AD patients.