Kaiyuan Zheng, Fotios N. Tsitsos, Alec J. Batts, Robin Ji, Tal Nuriel, Elisa E. Konofagou, Kam W. Leong
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The all-in-one clustered regularly interspaced short palindromic repeats (CRISPR)–based adeno-associated virus (AAV) vectors were administered intravenously at a dose of 1.5×10<sup>12</sup> vg per mouse to determine the gene-editing efficacy within the hippocampus.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>FUS-enhanced delivery of AAV resulted in a 12.6% knockdown of <i>APOE</i> 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.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our findings demonstrate a noninvasive, targeted approach for <i>APOE</i> ε4 knockdown, highlighting FUS-mediated brain-directed interventions as a promising therapeutic strategy for Alzheimer's disease.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Focused ultrasound (FUS) enables noninvasive, transient blood–brain barrier (BBB) opening for enhanced adeno-associated virus (AAV) delivery.</li>\n \n <li>FUS-mediated gene editing achieves a 12.6% knockdown in <i>APOE</i> ε4 expression within the hippocampus of mouse brain.</li>\n \n <li><i>APOE</i> ε4 knockdown significantly reduces apoE4 protein levels and astrocyte and microglia levels.</li>\n \n <li>No detectable gross toxicity was observed following the FUS-mediated gene editing.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 7","pages":""},"PeriodicalIF":13.0000,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70464","citationCount":"0","resultStr":"{\"title\":\"Focused ultrasound-mediated APOE4 knockdown in mouse brain\",\"authors\":\"Kaiyuan Zheng, Fotios N. 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Focused ultrasound-mediated APOE4 knockdown in mouse brain
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.
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.
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