中断的选择性剪接在神经系统疾病中起决定性作用,作为疾病易感性的直接原因或驱动因素。人类死后大脑样本的转录组学分析揭示了阿尔茨海默病(AD)大脑中数百个异常的mRNA剪接事件,将RNA剪接失调与疾病相关联。我们之前确定了跨载脂蛋白E受体2(APOER2)的可变剪接组合的复杂阵列,与神经保护配体Reelin和AD相关危险因素相互作用的跨膜受体,APOE.许多人类APOER2亚型,主要以功能重要结构域内的盒剪接事件为特征,对受体的功能和配体相互作用至关重要。然而,在生理和AD条件下,APOER2同工型的全面库和功能含义尚未完全了解。这里,我们对正常状态和AD状态下人类APOER2同工型的剪接景观进行了深入分析。使用单分子,长读测序,我们对BraakIV期AD脑组织的顶叶皮质和海马区的整个APOER2转录本以及年龄匹配的对照进行了分析,并研究了APOER2亚型的几种功能特性.我们的发现揭示了APOER2亚型的盒外显子跳跃的不同模式,其中一些表现出区域特异性表达,另一些表现出AD受影响的大脑特有的表达。值得注意的是,APOER2的外显子15,编码糖基化结构域,与对照相比,在AD中显示出较少的包涵体,在女性的顶叶皮层中具有APOE3/13C3基因型。此外,这些APOER2亚型中的一些表现出细胞表面表达的变化,APOE介导的受体加工,和突触数。这些变化可能在诱导突触改变中至关重要,并且可能导致AD发病机制的神经元功能障碍。
Disrupted alternative splicing plays a determinative role in neurological diseases, either as a direct cause or as a driver in disease susceptibility. Transcriptomic profiling of aged human postmortem brain samples has uncovered hundreds of aberrant mRNA splicing events in Alzheimer\'s disease (AD) brains, associating dysregulated RNA splicing with disease. We previously identified a complex array of alternative splicing combinations across apolipoprotein E receptor 2 (APOER2), a transmembrane receptor that interacts with both the neuroprotective ligand Reelin and the AD-associated risk factor, APOE. Many of the human APOER2 isoforms, predominantly featuring cassette splicing events within functionally important domains, are critical for the receptor\'s function and ligand interaction. However, a comprehensive repertoire and the functional implications of APOER2 isoforms under both physiological and AD conditions are not fully understood. Here, we present an in-depth analysis of the splicing landscape of human APOER2 isoforms in normal and AD states. Using single-molecule, long-read sequencing, we profiled the entire APOER2 transcript from the parietal cortex and hippocampus of Braak stage IV AD brain tissues along with age-matched controls and investigated several functional properties of APOER2 isoforms. Our findings reveal diverse patterns of cassette exon skipping for APOER2 isoforms, with some showing region-specific expression and others unique to AD-affected brains. Notably, exon 15 of APOER2, which encodes the glycosylation domain, showed less inclusion in AD compared to control in the parietal cortex of females with an APOE ɛ3/ɛ3 genotype. Also, some of these APOER2 isoforms demonstrated changes in cell surface expression, APOE-mediated receptor processing, and synaptic number. These variations are likely critical in inducing synaptic alterations and may contribute to the neuronal dysfunction underlying AD pathogenesis.