AUTHOR=Wu Hao , Wang Jiao , Hu Xiaoyuan , Zhuang Cheng , Zhou Jianxin , Wu Peiru , Li Shengli , Zhao Robert Chunhua 

TITLE=Comprehensive transcript-level analysis reveals transcriptional reprogramming during the progression of Alzheimer’s disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 15 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1191680

DOI=10.3389/fnagi.2023.1191680

ISSN=1663-4365

ABSTRACT=Alzheimer's disease (AD) is a common neurodegenerative disorder that has a multi-step disease progression. The differences between moderate AD and AD have yet been fully characterized. Herein, we performed a transcript-resolution analysis in 454 AD-related samples, including 145 non-demented control, 140 asymptomatic AD (AsymAD), and 169 AD samples. We comparatively characterized the trancriptome dysregulation in AsymAD and AD samples at transcript level. We identified 4,056 and 1,200 differentially spliced alternative splicing events (ASEs) that might play roles in the disease progression of AD and AsymAD, respectively. Our further analysis revealed 287 isoform switching events in AsymAD and 222 in AD. In particular, a total of 163 and 119 transcripts showed increased usage, while 124 and 103 transcripts exhibited decreased usage in AsymAD and AD, respectively. For example, gene APOA2 showed no expression changes between AD and non-demented control samples, but expressed higher proportion of transcript ENST00000367990.3 and lower proportion of transcript ENST00000463812.1 in AD compared to non-demented control samples. Furthermore, we constructed RNA binding protein (RBP)-ASE regulatory networks to reveal potential RBP-mediated isoform switch in AsymAD and AD. In summary, our study provided transcript-resolution insights into the transcriptome disturbance of AsymAD and AD, which will promote the early diagnosis and the development of new therapeutic strategies of patients with AD.