Brain-targeting liposome-based APOE2 gene delivery exacerbates soluble amyloid-β accumulation in App NL-G-F mice

• Published in: Heliyon 2024-10, Vol.10 (20), p.e39607
• Main Authors: Wang, Ni, Parsons, Tammee M, Ren, Yingxue, Pan, Yining, Kurti, Aishe, Starling, Skylar C, Muolokwu, Chinenye, Singh, Jagdish, Kanekiyo, Takahisa
• Format: Article
• Language: English
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e39607

Alzheimer's disease (AD) is the most common cause of late-life dementia characterized by progressive neurodegeneration and brain deposition of amyloid-β (Aβ) and phosphorylated tau. The ε2 encoding apolipoprotein E ( ) is a protective allele against AD among the three genotypes ( ε2, ε3, ε4), while is the strongest genetic factor substantially increasing AD risk. APOE regulates brain lipid homeostasis and maintaining synaptic plasticity and neuronal function, where has a superior function compared to and . Gene therapy that increases levels in the brain is, therefore, a promising therapeutic strategy for AD treatment. We previously reported that PEGylated liposomes conjugated with transferrin and a cell-penetrating peptide Penetratin sufficiently deliver chitosan-APOE2 cDNA plasmid complex into the brain of wild-type mice. Here, we investigated how brain-targeting liposome-based   gene delivery influences Aβ-related pathologies in amyloid model   knockin mice at 12-month-old. We found a trend of reductions of insoluble Aβ levels in the mouse cortices 1 month after gene therapy. Furthermore, in the knockin mice that received the gene therapy, brain transcriptome analysis through RNA-sequencing identified the upregulation of genes/pathways related to neuronal development. This was supported by increases of and mRNAs coding synaptic proteins in the experimental group. On the other hand, we found that gene delivery increased soluble Aβ levels, including oligomers, as well as exacerbated neurite dystrophy and decreased synaptophysin. Together, our results suggest that brain-targeting liposome-based gene therapy is potentially beneficial for synaptic formation at the transcriptional level. Forced expressions, however, may exacerbate Aβ toxicity by increasing the dissociation of Aβ oligomers from aggregates in the presence of considerable amyloid burden.