Comprehensive characterization of the RNA editing landscape in the human aging brains with Alzheimer's disease

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-09 DOI:10.1002/alz.70452

Amit Kumar Gupta, William Martin, Andrew A. Pieper, Yinsheng Wang, Andrew J. Saykin, Feixiong Cheng

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引用次数: 0

Abstract

INTRODUCTION

While RNA editing has been linked to Alzheimer's disease (AD), its specific impact on the transcriptomic landscape in human AD brains remains under explored.

METHODS

We conducted a comprehensive analysis of RNA editing across nine human brain regions affected by AD, utilizing RNA-seq data and matched whole-genome sequencing data from three human brain biobanks, adjusting for age, post mortem interval, sex, and apolipoprotein E4 (APOE4) status.

RESULTS

RNA-editing events were identified in both AD and healthy control aging brains, highlighting 127 genes with significant RNA editing loci. AD exhibited elevated RNA editing in the parahippocampal gyrus and cerebellar cortex. We also discovered 147 colocalized genome-wide association studies (GWAS) and cis-edQTL (± 1 MB) signals in 48 likely causal genes encompassing CLU, BIN1, and GRIN3B, primarily allied to amyloid and tau pathology, and neuroinflammation.

DISCUSSION

Our findings delineate RNA editing regulatory signatures in human AD, providing novel insights into AD pathophysiology and potential biomarkers and therapeutic targets.

Highlights

· We discovered genome-wide landscape of RNA editing signals from 4208 (1364 Alzheimer's disease [AD] cases vs. 742 healthy controls) RNA-seq data across nine human brain regions from three large brain biobanks (Mount Sinai Brain Bank [MSBB], Mayo Clinic [MAYO] Religious Order Study and Memory and Aging Project [ROSMAP]) tied with AD, including in sex-specific and apolipoprotein E4 (APOE4) -specific manner adjusting for age, post mortem interval (PMI), sex, and APOE4 status.
· We emphasize 127 genes, including SYT11, KCNIP4, NRG3, ANKS1B, and RALYL, exhibiting significant RNA editing loci shared by multiple brain tissues, mainly implicated in synaptic plasticity, signaling and transmission, neuronal development, and morphogenesis.
· Brain-wide tissue-specific cis-regulatory variants (cis-edQTLs) were inspected using matched genotyping data from 3627 samples from all brain biobanks. We revealed 147 colocalized AD-GWAS and cis-edQTLs signals pertaining to 48 likely causal genes comprising CLU (rs7982, rs1532278), BIN1 (rs2276582, rs3768863), GRIN3B (rs10417824, rs1058603), NYAP1 (rs12539172), DGKQ (rs4690197, rs3733347), CLPTM1 (rs204468), etc.
· Colocalized signals show affiliations to tau protein binding, amyloid-β regulation, cellular morphogenesis, and immune response pathway suggesting possible roles of epitranscriptomic mechanisms in shaping the AD risk.

Abstract Image

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人类阿尔茨海默病老化大脑中RNA编辑景观的综合表征

虽然RNA编辑与阿尔茨海默病（AD）有关，但其对人类AD大脑转录组学景观的具体影响仍有待探索。方法：我们利用来自三个人类大脑生物库的RNA-seq数据和匹配的全基因组测序数据，对受AD影响的9个人类大脑区域的RNA编辑进行了全面分析，调整了年龄、死后间隔、性别和载脂蛋白E4 （APOE4）状态。结果在阿尔茨海默病和健康对照的衰老大脑中都发现了RNA编辑事件，突出了127个具有显著RNA编辑位点的基因。AD表现出海马旁回和小脑皮层RNA编辑水平升高。我们还发现了147个共定位全基因组关联研究（GWAS）和48个可能的致病基因中的顺式edqtl（±1 MB）信号，包括CLU、BIN1和GRIN3B，主要与淀粉样蛋白和tau病理以及神经炎症有关。我们的研究结果描述了人类AD中的RNA编辑调控特征，为AD病理生理学和潜在的生物标志物和治疗靶点提供了新的见解。·我们发现了4208例（1364例阿尔茨海默病[AD]病例与742例健康对照）与AD相关的三个大型脑生物库（西奈山脑库[MSBB]，梅奥诊所[Mayo]宗教秩序研究和记忆与衰老项目[ROSMAP]）中9个人类大脑区域的RNA-seq数据的全基因组图谱。包括性别特异性和载脂蛋白E4 （APOE4）特异性的方式，调整年龄、死后间隔（PMI）、性别和APOE4状态。·我们强调127个基因，包括SYT11、KCNIP4、NRG3、ANKS1B和RALYL，在多个脑组织中表现出显著的RNA编辑位点，主要涉及突触可塑性、信号和传递、神经元发育和形态发生。·使用来自所有脑生物库的3627个样本的匹配基因分型数据检查全脑组织特异性顺式调节变异（cis-edQTLs）。我们发现147个共定位的AD-GWAS和cis-edQTLs信号与48个可能的致病基因有关，包括CLU （rs7982、rs1532278）、BIN1 （rs2276582、rs3768863）、GRIN3B （rs10417824、rs1058603）、NYAP1 （rs12539172）、DGKQ （rs4690197、rs3733347）、CLPTM1 （rs204468）等。共定位信号与tau蛋白结合、淀粉样蛋白β调控、细胞形态发生、和免疫反应途径提示在形成AD风险的表转录组机制中可能的作用。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.