Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection [spatial transcriptomics]. Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer's disease profile and possible mechanisms of disease protection [spatial transcriptomics]

Highly penetrant autosomal dominant Alzheimer's disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials. Overall design: We performed comparative gene expression profiling analysis using spatial transcriptomics data obtained from two different brain regions (frontal cortex and hippocampus) of post mortem brains of two patient carriers of the autosomal dominant PSEN-1E280A mutation and one healthy older control.

高外显率常染色体显性阿尔茨海默病（ADAD）属于一类独特的疾病亚型，相较于更为常见的、由多种常见变异共同介导发病风险的散发性阿尔茨海默病（AD），目前尚未深入探究在特定细胞类型中区分这两类AD的下游信号通路。我们对27例样本的单细胞核转录组进行了比较分析，样本分为三组：PSEN1-E280A突变携带者型ADAD、散发性AD患者以及健康对照。与散发性AD相比，自噬相关基因与分子伴侣可显著区分PSEN1-E280A突变型ADAD病例。空间转录组学验证了PSEN1-E280A突变型病例中分子伴侣介导的自噬基因的激活状态。1例PSEN1-E280A突变型ADAD病例，其大脑大部分区域未出现神经原纤维缠结病变，且携带纯合子APOE3-Christchurch变异，该病例为AD病理保护机制提供了潜在解释：包括星形胶质细胞中LRP1的过表达、FKBP1B表达上调，以及神经元中PSEN1表达下调。ADAD与散发性AD的独特细胞应答特征，在临床试验设计中需予以考量。实验整体设计：我们利用空间转录组学数据开展了比较基因表达谱分析，数据来源于2例携带常染色体显性PSEN-1E280A突变的患者死后脑组织，以及1例健康老年对照的两个不同脑区——额叶皮层与海马体。