| First Author | Condello C | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 4 | Pages | E782-E791 |
| PubMed ID | 29311311 | Mgi Jnum | J:260281 |
| Mgi Id | MGI:6113791 | Doi | 10.1073/pnas.1714966115 |
| Citation | Condello C, et al. (2018) Structural heterogeneity and intersubject variability of Abeta in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115(4):E782-E791 |
| abstractText | Point mutations in the amyloid-beta (Abeta) coding region produce a combination of mutant and WT Abeta isoforms that yield unique clinicopathologies in familial Alzheimer''s disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Abeta determines WT Abeta conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Abeta deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Abeta, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Abeta40 fibrils into transgenic mice expressing only WT Abeta induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Abeta40 prions induce a conformation of WT Abeta similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Abeta prion conformations, which kinetically dominate the spread of prions in the brain. |
