Splicing transcriptome analysis reveals retained introns in retinal genes of the 5xFAD mouse, suggesting early diagnosis of Alzheimers disease through vision impairment

Alzheimers disease (AD) is an age-related neurodegenerative disorder in which neuronal and synaptic loss of the brain leads to cognitive impairment and dementia. Therefore, the early diagnosis of AD with various biomarkers is important for the prevention and treatment. Although retina pathology is emerging biomarker that associated with AD, detailed molecular mechanisms of retinal impairments remain unclear. Here, we identify the genome-wide dysfunction of alternative splicing in the early stage of 5xFAD transgenic mouse retina by the RNA-seq analysis. Especially, retained intron (RI) highly enriched in phototransduction and retinal genes of 1.5-month-old 5xFAD mouse retina that significantly associated with retinal physiological impairment of rod photoreceptors by electroretinogram (ERG) analysis. These results indicate that the abnormal scotopic ERG associated with global splicing impairment may be useful early detection biomarker for AD. We compared transcript and retained intron expression profiles between mouse retina of wild type and 5xFAD. RNA-seq for 1-month and 6-month were performed in mouse retina between wild type and 5xFAD.阿尔茨海默病（Alzheimers disease, AD）是一种年龄相关性神经退行性疾病，患者大脑出现神经元与突触丢失，进而引发认知障碍与痴呆。因此，借助各类生物标志物实现AD的早期诊断，对疾病的预防与治疗具有重要意义。尽管视网膜病理已成为与AD相关的新兴生物标志物，但视网膜损伤的具体分子机制仍未明确。本研究通过RNA测序（RNA-seq）分析，明确了1.5月龄5xFAD转基因小鼠视网膜在疾病早期阶段的全基因组可变剪接异常。尤为关键的是，在1.5月龄5xFAD转基因小鼠视网膜的光转导相关基因与视网膜基因中，内含子滞留（retained intron, RI）的富集程度显著升高；结合视网膜电图（Electroretinogram, ERG）分析结果，该现象与杆状光感受器的视网膜生理功能损伤密切相关。上述结果表明，与全局剪接异常相关的异常暗适应视网膜电图，或可作为AD的有效早期检测生物标志物。本研究对比了野生型（Wild Type, WT）与5xFAD转基因小鼠视网膜的转录本及内含子滞留表达谱，并针对1月龄与6月龄的野生型及5xFAD转基因小鼠视网膜开展了RNA测序实验。