Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.

中文翻译：

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阿尔茨海默病的内毒素假说


脂多糖（LPS）构成了革兰氏阴性细菌表面的大部分，如果LPS进入人体或大脑，会引起炎症并充当内毒素。我们在这里概述了这样的假设：LPS 可能通过外周感染或肠道功能障碍，提高血液和大脑中的 LPS 水平，从而促进：淀粉样蛋白病理、tau 病理和小胶质细胞激活，从而导致 AD 的神经变性，从而导致阿尔茨海默病 (AD) 的病理生理学。支持这一假设的证据包括：i) AD 患者血液和大脑中的 LPS 水平升高，ii) AD 危险因素增加 LPS 水平或反应，iii) LPS 诱导 Aβ 表达、聚集、炎症和神经毒性，iv) LPS 诱导 TAU v) LPS 诱导小胶质细胞启动、激活和神经毒性，vi) 血液 LPS 导致 AD 小鼠模型突触、神经元和记忆丧失，以及人类认知功能障碍。然而，为了检验这一假设，有必要检验减少血液 LPS 是否会降低 AD 风险或进展。如果 LPS 内毒素假说正确，那么治疗方法可能包括：减少感染、改变肠道微生物组、减少肠漏、降低血液 LPS 或阻断 LPS 反应。