APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes

IF 11.1 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's & Dementia Pub Date : 2025-01-29 DOI:10.1002/alz.14560

Srishruthi Thirumalai, Frederick J. Livesey, Rickie Patani, Christy Hung

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Abstract

INTRODUCTION

Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).

METHODS

Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.

RESULTS

APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.

DISCUSSION

APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.

Highlights

APP ASOs reduce APP levels in human iPSC-derived astrocytes.
APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes.
This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.

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APP反义寡核苷酸对人类ipsc衍生的21三体星形细胞线粒体表型的修复是有效的

反义寡核苷酸（ASOs）在降低神经元中淀粉样前体蛋白（APP）水平方面显示出前景，但它们在星形胶质细胞中的作用仍不清楚，星形胶质细胞是神经退行性疾病的关键因素。本研究评估了APP ASOs对来自唐氏综合征（DS）患者的星形胶质细胞的疗效，唐氏综合征是阿尔茨海默病（AD）的高危人群。

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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.