Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
Gladstone Center for Translational Advancement, San Francisco, CA, USA.
Nat Neurosci. 2021 Jun;24(6):786-798. doi: 10.1038/s41593-021-00851-3. Epub 2021 May 6.
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.
选择性神经退行性变是阿尔茨海默病（AD）的一个关键致病因素；然而，导致一些神经元死亡，而另一些神经元保持弹性的机制尚不清楚。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，发现 ApoE 表达水平是神经元变异性的一个重要驱动因素。引人注目的是，ApoE 在神经元中的表达——与 AD 有很强的遗传关联——在野生型小鼠、人类 ApoE 基因敲入小鼠和有或没有 AD 的人类大脑中的神经元免疫反应途径上，在单细胞基础上强烈相关。神经元 ApoE 的消除或过表达揭示了 ApoE 表达、神经元 MHC-I 表达、tau 病理学和神经退行性变之间的因果关系。MHC-I 的功能降低可改善 ApoE4 表达的原代神经元和表达病理性 tau 的小鼠海马中的 tau 病理学。这些发现表明，一种将神经元 ApoE 表达与 MHC-I 表达联系起来的机制，进而与 tau 病理学和选择性神经退行性变联系起来。
