Constipation in Tg2576 mice model for Alzheimer’s disease associated with dysregulation of mechanism involving the mAChR signaling pathway and ER stress response

BackgroundAlthough constipation has been researched in various neurological disorders, including Parkinson’s disease (PD) and spinal cord injury (SCI), the pathological mechanism of this symptom has not been investigated in Alzheimer’s disease (AD) associated with loss of nerve cells in the brain. This study was undertaken to gain scientific evidences for a molecular correlation between constipation and AD.MethodsTo understand the etiology, we measured alterations in various constipation parameters, muscarinic acetylcholine receptors (mAChRs) and endoplasmic reticulum (ER) stress response, in 11-month-old Tg2576 transgenic (Tg) mice showing AD-like phenotypes.ResultsA high accumulation of amyloid beta (Aβ) peptides, a key marker of AD pathology, were detected in the cortex and hippocampus of Tg mice. Furthermore, significant alterations were observed in various constipation parameters including stool weight, histological structure, cytological structure and mucin secretion in Tg2576 mice. Moreover, M2 and M3 expression and the downstream signaling pathways of mAChRs were decreased in the Tg group, as compared with non-Tg (NT) group. Furthermore, activation of ER stress proteins and alteration of ER structure were also detected in the same group.ConclusionsThe results of the present study provide strong novel evidence that the neuropathological constipation detected in Tg2576 mice is linked to dysregulation of the mAChR signaling pathways and ER stress response.背景 尽管便秘已在包括帕金森病（Parkinson’s disease, PD）和脊髓损伤（spinal cord injury, SCI）在内的多种神经系统疾病中得到研究，但对于与大脑神经细胞丢失相关的阿尔茨海默病（Alzheimer’s disease, AD）中该症状的病理机制，目前仍未开展相关探究。本研究旨在为便秘与阿尔茨海默病之间的分子关联提供科学依据。 方法 为明确其病因学机制，本研究对表现出类阿尔茨海默病表型的11月龄Tg2576转基因（transgenic, Tg）小鼠，开展了多项便秘相关参数、毒蕈碱型乙酰胆碱受体（muscarinic acetylcholine receptors, mAChRs）以及内质网（endoplasmic reticulum, ER）应激反应的变化检测。 结果 研究人员在转基因小鼠的大脑皮层与海马体中，检测到了作为阿尔茨海默病病理核心标志物的β淀粉样蛋白（amyloid beta, Aβ）大量聚集。此外，Tg2576转基因小鼠的多项便秘相关参数均出现显著变化，包括粪便重量、组织学结构、细胞学结构以及黏蛋白分泌水平。与非转基因（non-Tg, NT）对照组相比，转基因组小鼠的毒蕈碱型乙酰胆碱受体M2、M3亚型表达及其下游信号通路均出现下调。同时，该组小鼠还检测到内质网应激蛋白激活以及内质网结构异常改变。 结论 本研究结果提供了强有力的全新证据，表明Tg2576小鼠中出现的神经病理性便秘与毒蕈碱型乙酰胆碱受体信号通路失调以及内质网应激反应异常存在关联。