Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD).
Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD).
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发表时间：
2015-07
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通讯作者：
Yuhai Zhao;W. Lukiw
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作者：
Yuhai Zhao;W. Lukiw
根据16年前首次提出的“阿尔茨海默病淀粉样蛋白级联假说”，Aβ肽在中枢神经系统（CNS）中的积累是阿尔茨海默病（AD）发病的主要影响因素，Aβ肽的积累是Aβ肽产生和清除失衡的结果。在过去的18个月里，多个实验室报告了两个特别重要的观察结果：（i）由于人类微生物组的微生物天然分泌大量淀粉样蛋白、脂多糖（LPS）和其他相关的促炎致病信号，这些可能有助于老年人的全身和CNS淀粉样蛋白负担;和（ii）Aβ肽的清除似乎因小胶质细胞/髓样-2细胞中表达的小胶质细胞质膜富集触发受体（TREM 2）缺陷而内在受损。这篇简短的一般性评论观点论文：（i）将突出一些关于微生物组分泌的淀粉样蛋白和LPS的最新发现，以及这些微生物源性促炎和神经毒性渗出物对宿主中年龄相关性炎症和AD型神经变性的潜在贡献;和（ii）将讨论基于小胶质细胞的TREM 2跨膜传感器缺陷的贡献-与Aβ肽从人CNS的正常稳态清除相反，Aβ肽在AD中的淀粉样蛋白生成的受体系统中起作用。
According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Aβ peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Aβ peptide accretion is the result of an imbalance between Aβ peptide production and clearance. In the last 18 months multiple laboratories have reported two particularly important observations: (i) that because the microbes of the human microbiome naturally secrete large amounts of amyloid, lipopolysaccharides (LPS) and other related pro-inflammatory pathogenic signals, these may contribute to both the systemic and CNS amyloid burden in aging humans; and (ii) that the clearance of Aβ peptides appears to be intrinsically impaired by deficits in the microglial plasma-membrane enriched triggering receptor expressed in microglial/myeloid-2 cells (TREM2). This brief general commentary-perspective paper: (i) will highlight some of these very recent findings on microbiome-secreted amyloids and LPS and the potential contribution of these microbial-derived pro-inflammatory and neurotoxic exudates to age-related inflammatory and AD-type neurodegeneration in the host; and (ii) will discuss the contribution of a defective microglial-based TREM2 transmembrane sensor-receptor system to amyloidogenesis in AD that is in contrast to the normal, homeostatic clearance of Aβ peptides from the human CNS.