Focused ultrasound-mediated APOE4 knockdown in mouse brain

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-15 DOI:10.1002/alz.70464

Kaiyuan Zheng, Fotios N. Tsitsos, Alec J. Batts, Robin Ji, Tal Nuriel, Elisa E. Konofagou, Kam W. Leong

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Abstract

INTRODUCTION

The apolipoprotein E (APOE) ε4 allele is widely recognized as the strongest genetic risk factor for late-onset Alzheimer's disease. Therapeutic strategies to reduce apoE4 expression in APOE ε4 carriers hold promise to mitigate neuroinflammatory and neurodegenerative processes driving disease progression.

METHODS

Focused ultrasound (FUS) was employed to transiently open the blood–brain barrier (BBB) for efficient knockdown of humanized APOE ε4 in the mouse brain via gene editing. The all-in-one clustered regularly interspaced short palindromic repeats (CRISPR)–based adeno-associated virus (AAV) vectors were administered intravenously at a dose of 1.5×10¹² vg per mouse to determine the gene-editing efficacy within the hippocampus.

RESULTS

FUS-enhanced delivery of AAV resulted in a 12.6% knockdown of APOE ε4 gene expression in the targeted hippocampus, accompanied by an over 20% decrease in apoE4 protein levels and significant reductions in astrocyte and microglia levels.

DISCUSSION

Our findings demonstrate a noninvasive, targeted approach for APOE ε4 knockdown, highlighting FUS-mediated brain-directed interventions as a promising therapeutic strategy for Alzheimer's disease.

Highlights

Focused ultrasound (FUS) enables noninvasive, transient blood–brain barrier (BBB) opening for enhanced adeno-associated virus (AAV) delivery.
FUS-mediated gene editing achieves a 12.6% knockdown in APOE ε4 expression within the hippocampus of mouse brain.
APOE ε4 knockdown significantly reduces apoE4 protein levels and astrocyte and microglia levels.
No detectable gross toxicity was observed following the FUS-mediated gene editing.

Abstract Image

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聚焦超声介导的小鼠脑APOE4基因敲除

载脂蛋白E (APOE) ε4等位基因被广泛认为是迟发性阿尔茨海默病最强的遗传危险因素。降低APOE ε4携带者apoE4表达的治疗策略有望缓解驱动疾病进展的神经炎症和神经退行性过程。方法利用聚焦超声（Focused ultrasound， FUS）瞬时打开血脑屏障（blood-brain barrier， BBB），通过基因编辑高效敲除小鼠大脑人源化APOE ε4。以每只小鼠1.5×1012 vg的剂量静脉注射基于短回文重复（CRISPR）的all-in-one集群规则间隔短回文重复（short palindromic repeats， CRISPR）的腺相关病毒（adeno-associated virus， AAV）载体，以确定海马内的基因编辑效果。结果：经fus增强的AAV递送导致靶海马APOE ε4基因表达下调12.6%，apoE4蛋白水平降低20%以上，星形胶质细胞和小胶质细胞水平显著降低。我们的研究结果证明了一种无创的、靶向的APOE ε4敲低方法，强调了fus介导的脑定向干预是治疗阿尔茨海默病的一种有前景的治疗策略。聚焦超声（FUS）能够无创、短暂的血脑屏障（BBB）打开，增强腺相关病毒（AAV）的传递。fus介导的基因编辑实现了小鼠脑海马内APOE ε4表达下调12.6%。APOE ε4敲低可显著降低apoE4蛋白水平及星形胶质细胞和小胶质细胞水平。在fus介导的基因编辑后，未观察到可检测到的总体毒性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.