School of Biomedical Sciences.
Faculty of Medicine the Laboratory Animal Services Centre, The Chinese University of Hong Kong, New Territories, Hong Kong.
J Physiol. 2020 Oct;598(19):4209-4223. doi: 10.1113/JP279919. Epub 2020 Jul 6.
Alzheimer's disease (AD) patients and transgenic mice have beta-amyloid (Aβ) aggregation in the gastrointestinal (GI) tract. It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion-like properties. The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β-amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits. These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD.
Alzheimer's disease (AD) is the most common age-related cause of dementia, characterised by extracellular beta-amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra-GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD-related pathology such as dementia. We micro-injected Aβ1-42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555-labelled Aβ1-42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555-labelled Aβ1-42 in the body of the stomach and proximal colon had partly re-distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y-maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD-like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD.
阿尔茨海默病（AD）患者和转基因小鼠的胃肠道（GI）中有β-淀粉样蛋白（Aβ）聚集。外周 Aβ 可能有助于大脑中 Aβ 的负荷，因为 Aβ 具有朊病毒样特性。本研究表明，注射到 ICR 小鼠胃肠道中的 Aβ 被内化到肠胆碱能神经元中；1 个月时，观察到 Aβ 注射到胃体和近端结肠部分重新分布到胃底和空肠；1 年后，出现了迷走神经和大脑β-淀粉样变性，并且小鼠表现出胃肠道功能障碍和认知缺陷。这些数据揭示了一种以前未被发现的机制，可能有助于 AD 的发展。
阿尔茨海默病（AD）是最常见的与年龄相关的痴呆症病因，其特征是脑外的β-淀粉样蛋白（Aβ）斑块和细胞内磷酸化 tau 缠结。AD 患者和转 AD 基因的小鼠的胃肠道（GI）中也观察到 Aβ 沉积，其淀粉样前体蛋白过度表达。在本研究中，我们研究了 GI 内注射 Aβ 是否可能在中枢神经系统（CNS）中诱导淀粉样变性以及与痴呆相关的 AD 相关病理学，如痴呆。我们在全身麻醉下将 Aβ1-42 寡聚物（每个部位 4μg，5 个部位）或载体（盐水，5μl）微注射到 ICR 小鼠的胃壁中。免疫荧光染色和体内成像显示，HiLyte Fluor 555 标记的 Aβ1-42 在 3 小时内通过黏膜下层迁移到附近区域，并被内化到胆碱能神经元中。1 个月时，胃体和近端结肠中的 HiLyte Fluor 555 标记的 Aβ1-42 已部分重新分布到胃底和空肠。1 年后，空肠的神经肌肉偶联出现功能改变（P<0.001），迷走神经和大脑中出现 Aβ 沉积，动物在 Y 型迷宫自发改变测试（P<0.001）和新物体识别测试（P<0.001）中表现出认知障碍。我们发现，肠内 Aβ 寡聚物通过迷走神经机制引起胃功能改变、CNS 淀粉样变性和 AD 样痴呆。我们的结果表明，Aβ 负荷可能首先发生在胃肠道，并可能转移到大脑，为 AD 的早期诊断和预防开辟了新的策略。
