MicroRNA cargo in neuron-derived vesicles as peripheral biomarkers of brain insulin dysregulation

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-09-17 DOI:10.1002/alz.70597

Jacob Alexander Cleary, Ashish Kumar, Yixin Su, Sangeeta Singh, Fang-Chi Hsu, Suzanne Craft, William Harrison, C. Dirk Keene, Marjorie Howard, Kathleen M. Hayden, Mark A. Espeland, Jingzhong Ding, Gagan Deep

{"title":"MicroRNA cargo in neuron-derived vesicles as peripheral biomarkers of brain insulin dysregulation","authors":"Jacob Alexander Cleary, Ashish Kumar, Yixin Su, Sangeeta Singh, Fang-Chi Hsu, Suzanne Craft, William Harrison, C. Dirk Keene, Marjorie Howard, Kathleen M. Hayden, Mark A. Espeland, Jingzhong Ding, Gagan Deep","doi":"10.1002/alz.70597","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>Brain insulin resistance (bIR) is a risk factor for Alzheimer's disease (AD). However, the association between bIR and peripheral insulin resistance and their effects on cognition remains unclear.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>Here, we analyzed the expression of key genes (<i>n</i> = 84) involved in insulin signaling in brain tissue collected from healthy and AD subjects, as well as regulatory microRNAs (miRNAs) in the brain tissue and tissue-derived small extracellular vesicles (sEV). Subsequently, miRNA expression was analyzed in plasma neuron-derived sEV (NDE) of a second cohort consisting of cognitively normal and adjudicated mixed dementia (aMD) subjects, all with type 2 diabetes.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Analysis of miRNAs in brain tissue and their sEV revealed significant and concordant dysregulation. NDE demonstrated similar changes in specific miRNA expression, with significant upregulation exclusively in male aMD subjects, and showed correlation with cognition and plasma β-amyloid (Aβ) 1-40 and Aβ1-42.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>NDE may serve as a liquid biopsy to determine sex-specific bIR and cognitive impairment.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Insulin signaling is disrupted in brain tissue with Alzheimer's disease (AD).</li>\n \n <li>microRNAs (miRNAs) regulate insulin signaling and insulin resistance.</li>\n \n <li>miRNAs in neuron-derived small extracellular vesicles (sEV) could serve as biomarkers for brain insulin signaling.</li>\n \n <li>Brain insulin signaling biomarkers in neuron-derived sEV (NDE) could predict cognitive impairment.</li>\n \n <li>Sex-specific differences exist in brain insulin resistance biomarkers.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 9","pages":""},"PeriodicalIF":11.1000,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441806/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's & Dementia","FirstCategoryId":"3","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70597","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

INTRODUCTION

Brain insulin resistance (bIR) is a risk factor for Alzheimer's disease (AD). However, the association between bIR and peripheral insulin resistance and their effects on cognition remains unclear.

METHODS

Here, we analyzed the expression of key genes (n = 84) involved in insulin signaling in brain tissue collected from healthy and AD subjects, as well as regulatory microRNAs (miRNAs) in the brain tissue and tissue-derived small extracellular vesicles (sEV). Subsequently, miRNA expression was analyzed in plasma neuron-derived sEV (NDE) of a second cohort consisting of cognitively normal and adjudicated mixed dementia (aMD) subjects, all with type 2 diabetes.

RESULTS

Analysis of miRNAs in brain tissue and their sEV revealed significant and concordant dysregulation. NDE demonstrated similar changes in specific miRNA expression, with significant upregulation exclusively in male aMD subjects, and showed correlation with cognition and plasma β-amyloid (Aβ) 1-40 and Aβ1-42.

DISCUSSION

NDE may serve as a liquid biopsy to determine sex-specific bIR and cognitive impairment.

Highlights

Insulin signaling is disrupted in brain tissue with Alzheimer's disease (AD).
microRNAs (miRNAs) regulate insulin signaling and insulin resistance.
miRNAs in neuron-derived small extracellular vesicles (sEV) could serve as biomarkers for brain insulin signaling.
Brain insulin signaling biomarkers in neuron-derived sEV (NDE) could predict cognitive impairment.
Sex-specific differences exist in brain insulin resistance biomarkers.

Abstract Image

查看原文本刊更多论文

神经元源性囊泡中的MicroRNA装载作为脑胰岛素失调的外周生物标志物。

脑胰岛素抵抗（bIR）是阿尔茨海默病（AD）的危险因素之一。然而，bIR与外周胰岛素抵抗之间的关系及其对认知的影响尚不清楚。方法：在这里，我们分析了从健康和AD受试者收集的脑组织中参与胰岛素信号传导的关键基因（n = 84）的表达，以及脑组织和组织源性小细胞外囊泡（sEV）中的调控性microrna （miRNAs）的表达。随后，研究人员分析了第二组认知正常和确诊混合性痴呆（aMD）受试者的血浆神经元源性sEV （NDE）中miRNA的表达，这些受试者均患有2型糖尿病。结果：脑组织中mirna及其sEV分析显示显著且一致的失调。NDE在特异性miRNA表达方面也表现出类似的变化，仅在男性aMD受试者中显著上调，并与认知和血浆β-淀粉样蛋白（Aβ） 1-40和Aβ1-42相关。讨论：濒死体验可以作为液体活检来确定性别特异性bIR和认知障碍。重点：阿尔茨海默病（AD）患者的脑组织中胰岛素信号被破坏。microrna （mirna）调节胰岛素信号传导和胰岛素抵抗。神经元来源的小细胞外囊泡（sEV）中的mirna可作为脑胰岛素信号传导的生物标志物。神经元源性sEV （NDE）脑胰岛素信号生物标志物可预测认知障碍。脑胰岛素抵抗生物标志物存在性别特异性差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

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.