| First Author | Ye L | Year | 2017 |
| Journal | EMBO Rep | Volume | 18 |
| Issue | 9 | Pages | 1536-1544 |
| PubMed ID | 28701326 | Mgi Jnum | J:249736 |
| Mgi Id | MGI:5926041 | Doi | 10.15252/embr.201744067 |
| Citation | Ye L, et al. (2017) Abeta seeding potency peaks in the early stages of cerebral beta-amyloidosis. EMBO Rep 18(9):1536-1544 |
| abstractText | Little is known about the extent to which pathogenic factors drive the development of Alzheimer's disease (AD) at different stages of the long preclinical and clinical phases. Given that the aggregation of the beta-amyloid peptide (Abeta) is an important factor in AD pathogenesis, we asked whether Abeta seeds from brain extracts of mice at different stages of amyloid deposition differ in their biological activity. Specifically, we assessed the effect of age on Abeta seeding activity in two mouse models of cerebral Abeta amyloidosis (APPPS1 and APP23) with different ages of onset and rates of progression of Abeta deposition. Brain extracts from these mice were serially diluted and inoculated into host mice. Strikingly, the seeding activity (seeding dose SD50) in extracts from donor mice of both models reached a plateau relatively early in the amyloidogenic process. When normalized to total brain Abeta, the resulting specific seeding activity sharply peaked at the initial phase of Abeta deposition, which in turn is characterized by a temporary several-fold increase in the Abeta42/Abeta40 ratio. At all stages, the specific seeding activity of the APPPS1 extract was higher compared to that of APP23 brain extract, consistent with a more important contribution of Abeta42 than Abeta40 to seed activity. Our findings indicate that the Abeta seeding potency is greatest early in the pathogenic cascade and diminishes as Abeta increasingly accumulates in brain. The present results provide experimental support for directing anti-Abeta therapeutics to the earliest stage of the pathogenic cascade, preferably before the onset of amyloid deposition. |
