| First Author | Park KW | Year | 2021 |
| Journal | Mol Ther | Volume | 29 |
| Issue | 7 | Pages | 2294-2307 |
| PubMed ID | 33647457 | Mgi Jnum | J:358100 |
| Mgi Id | MGI:7735315 | Doi | 10.1016/j.ymthe.2021.02.026 |
| Citation | Park KW, et al. (2021) Gene therapy using Abeta variants for amyloid reduction. Mol Ther 29(7):2294-2307 |
| abstractText | Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid beta (Abeta) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Abeta variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Abeta in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Abeta oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Abeta levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Abeta variants may offer a novel therapeutic strategy for Alzheimer's disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases. |
