小柯机器人

美国格拉德斯通神经病研究所Yadong Huang和Kelly A. Zalocusky课题组合作取得一项新突破。他们发现神经元ApoE上调MHC-I表达，以驱动阿尔茨海默氏病（AD）的选择性神经退行性变。这一研究成果于2021年5月6日发表在国际顶尖学术期刊《自然-神经科学》杂志上。

我们使用单核RNA测序寻找这种选择性脆弱性的潜在驱动因素，并发现ApoE表达水平是神经元变异性的重要驱动因素。令人惊讶的是，ApoE（与AD具有牢固的遗传联系）的神经元表达在逐个细胞的基础上与野生型小鼠、人类ApoE敲入小鼠和有或没有AD的人联系紧密。神经元ApoE的消除或过表达揭示了ApoE表达，神经元MHC-1表达，tau病理学和神经变性之间的因果关系。

在表达ApoE4的原代神经元和表达病理性tau的小鼠海马体中，MHC-1的功能降低可改善tau病理。这些发现表明了将神经元ApoE表达与MHC-1表达以及随后的tau病理学和选择性神经变性联系起来的机制。

据介绍，选择性神经变性是AD的关键原因。但是，导致某些神经元灭亡而其他神经元保持弹性的机制尚不清楚。

附：英文原文

Title: Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease

Author: Kelly A. Zalocusky, Ramsey Najm, Alice L. Taubes, Yanxia Hao, Seo Yeon Yoon, Nicole Koutsodendris, Maxine R. Nelson, Antara Rao, David A. Bennett, Jason Bant, Dah-eun J. Amornkul, Qin Xu, Alice An, Olga Cisne-Thomson, Yadong Huang

Issue&Volume: 2021-05-06

Abstract: Selective neurodegeneration is a critical causal factor in Alzheimer’s disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE—which has a robust genetic linkage to AD—correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

DOI: 10.1038/s41593-021-00851-3

Source: https://www.nature.com/articles/s41593-021-00851-3

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