小柯机器人

厦门大学教授Xin Wang团队近期取得重要工作进展，他们研究发现β2-微球蛋白与Aβ共同聚集会导致阿尔茨海默病模型小鼠的淀粉样蛋白病理和认知缺陷。相关研究成果2023年6月1日在线发表于《自然—神经科学》杂志上。

据介绍，广泛的研究表明，β-淀粉样蛋白（Aβ）聚集是阿尔茨海默病（AD）进展的关键。然而，越来越多的证据表明，Aβ本身不足以引发AD相关的变性，是否其他额外的病理因素驱动AD的发病机制尚不清楚。

研究人员描述了由β₂-微球蛋白（β₂M）和Aβ组成的致病聚集体，它们触发AD的神经退行性变。β₂M是主要组织相容性复合体I类（MHC I类）的一种成分，在AD患者的大脑中上调，并构成淀粉样斑块核心。β₂M的升高会加重淀粉样蛋白病理，而不依赖于MHC I类，与β₂M共同聚集对Aβ神经毒性至关重要。B2m基因消融消除了AD小鼠的淀粉样蛋白扩散和认知缺陷。反义寡核苷酸或单克隆抗体介导的β₂M缺失可缓解AD相关神经病理学，抑制β₂M–Aβ与基于β₂M阻断肽的共聚集可改善AD小鼠的淀粉样蛋白病理和认知缺陷。

总之，这一研究结果表明，β₂M是Aβ神经毒性的重要因子，也是治疗AD的潜在靶点。

附：英文原文

Title: β2-Microglobulin coaggregates with Aβ and contributes to amyloid pathology and cognitive deficits in Alzheimer’s disease model mice

Author: Zhao, Yini, Zheng, Qiuyang, Hong, Yujuan, Gao, Yue, Hu, Jiaojiao, Lang, Maoju, Zhang, Hongfeng, Zhou, Ying, Luo, Hong, Zhang, Xian, Sun, Hao, Yan, Xiao-Xin, Huang, Timothy Y., Wang, Yan-Jiang, Xu, Huaxi, Liu, Cong, Wang, Xin

Issue&Volume: 2023-06-01

Abstract: Extensive studies indicate that β-amyloid (Aβ) aggregation is pivotal for Alzheimer’s disease (AD) progression; however, cumulative evidence suggests that Aβ itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of β2-microglobulin (β2M) and Aβ that trigger neurodegeneration in AD. β2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of β2M aggravates amyloid pathology independent of MHC class I, and coaggregation with β2M is essential for Aβ neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated β2M depletion mitigates AD-associated neuropathology, and inhibition of β2M–Aβ coaggregation with a β2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify β2M as an essential factor for Aβ neurotoxicity and a potential target for treating AD.

DOI: 10.1038/s41593-023-01352-1

Source: https://www.nature.com/articles/s41593-023-01352-1

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex