Abstract |
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 β (Aβ) 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 Aβ 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 Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ 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 Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ 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.
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Authors | Kyung-Won Park, Caleb A Wood, Jun Li, Bethany C Taylor, SaeWoong Oh, Nicolas L Young, Joanna L Jankowsky |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 29
Issue 7
Pg. 2294-2307
(07 07 2021)
ISSN: 1525-0024 [Electronic] United States |
PMID | 33647457
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved. |
Chemical References |
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Topics |
- Alzheimer Disease
(genetics, pathology, therapy)
- Amyloid beta-Peptides
(antagonists & inhibitors, genetics, metabolism)
- Animals
- Brain
(metabolism)
- Dependovirus
(genetics)
- Female
- Genetic Therapy
- Genetic Vectors
(administration & dosage, genetics)
- Humans
- Male
- Mice
- Mice, Inbred ICR
- Mice, Transgenic
- Mutation
- Plaque, Amyloid
(genetics, metabolism, therapy)
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