Neuronal ApoE Upregulates MHC-I Expression to Drive Selective Neurodegeneration in Alzheimer's Disease

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish while 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 wildtype mice, human apoE knock-in mice, and humans with or without AD. Elimination or over-expression of neuronal apoE revealed a causal relationship between 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. Overall design: Single-nucleus RNA sequencing of hippocampus from human APOE3 targeted replacement mice at 5, 10, 15, and 20 months, human APOE4 targeted replacement mice at 5, 10, 15, and 20 months, and neuron-specific APOE-KO (Syn-cre x floxed APOE) mice at 10 and 15 months.

选择性神经退行性变是阿尔茨海默病（AD）的关键致病因素，但目前尚不明确为何部分神经元发生凋亡而其余神经元仍能保持存活。本研究借助单细胞核RNA测序（single-nucleus RNA sequencing）探索了这种选择性易损性的潜在驱动因素，发现载脂蛋白E（apolipoprotein E, apoE）的表达水平是神经元异质性的关键驱动因子。值得注意的是，与AD存在强遗传关联的神经元源性apoE表达，在单细胞分辨率水平下，与野生型小鼠、人源apoE敲入小鼠以及罹患或未罹患AD的人类大脑神经元中的免疫应答通路显著相关。敲除或过表达神经元源性apoE的实验证实，apoE表达、神经元主要组织相容性复合体I类（major histocompatibility complex class I, MHC-I）表达、Tau病理（Tau pathology）与神经退行性变之间存在因果关联。功能性抑制MHC-I表达可减轻表达载脂蛋白E4（apoE4）的原代神经元以及携带病理性Tau的小鼠海马体中的Tau病理损伤。上述研究结果揭示了一条潜在机制：神经元源性apoE表达先调控MHC-I表达，进而影响Tau病理进程与选择性神经退行性变。实验整体设计：对5、10、15、20月龄的人源APOE3靶向替换小鼠、人源APOE4靶向替换小鼠，以及10、15月龄的神经元特异性APOE敲除（Syn-cre × floxed APOE）小鼠的海马体开展单细胞核RNA测序。