| Autor: |
Kumar R; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden., Arroyo-García LE; Division of Neurogeriatrics; Center for Alzheimer Research; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 64 Solna, Sweden.; Department of Women's and Children's Health, Karolinska Institutet, 171 64 Solna, Sweden., Manchanda S; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden., Adam L; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden., Pizzirusso G; Division of Neurogeriatrics; Center for Alzheimer Research; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 64 Solna, Sweden.; Department of Women's and Children's Health, Karolinska Institutet, 171 64 Solna, Sweden., Biverstål H; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden., Nilsson P; Division of Neurogeriatrics; Center for Alzheimer Research; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 64 Solna, Sweden., Fisahn A; Division of Neurogeriatrics; Center for Alzheimer Research; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 64 Solna, Sweden., Johansson J; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden., Abelein A; Department of Biosciences and Nutrition, Karolinska Institutet, 141 52 Huddinge, Sweden. |
| Abstrakt: |
Self-replication of amyloid-β-peptide (Aβ) fibril formation is a hallmark in Alzheimer's disease (AD). Detailed insights have been obtained in Aβ self-assembly in vitro, yet whether similar mechanisms are relevant in vivo has remained elusive. Here, we investigated the ability of in vivo-derived Aβ fibrils from two different amyloid precursor protein knock-in AD mouse models to seed Aβ42 aggregation, where we quantified the microscopic rate constants. We found that the nucleation mechanism of in vivo-derived fibril-seeded Aβ42 aggregation can be described with the same kinetic model as that in vitro. Further, we identified the inhibitory mechanism of the anti-amyloid BRICHOS chaperone on seeded Aβ42 fibrillization, revealing a suppression of secondary nucleation and fibril elongation, which is strikingly similar as observed in vitro. These findings hence provide a molecular understanding of the Aβ42 nucleation process triggered by in vivo-derived Aβ42 propagons, providing a framework for the search for new AD therapeutics. |
