ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
Focused ultrasound-mediated APOE4 knockdown in mouse brain.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Focused ultrasound-mediated lipid nanoparticle delivery for brain gene editing.Molecular therapy. Nucleic acids · 2026Article
- Beyond Lipidation: CSF APOE4 Protein Burden, Not HDL Subclass, Drives Tau Associations in APOE4 Alzheimer's Disease.Research square · 2026Article
- Focused ultrasound-mediated APOE4 knockdown in mouse brain.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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Authors and funding
7 authors.
Funding
Abstract
introductionThe 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.
methodsFocused 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 1.5×10
resultsFUS-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.
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