Contributed by William F. DeGrado, December 5, 2017 (sent for review August 30, 2017; reviewed by Wilfredo Colón and David M. Holtzman)
An expanding body of evidence argues that the Aβ and tau proteins share important characteristics of prion propagation to cause pathogenesis in Alzheimer’s disease (AD). Aβ and tau form a number of amyloids (β-sheet–rich structures) with distinct conformations (“strains”), some of which give rise to different diseases and associated pathologies. We develop new probes of amyloid structure and use these to identify conformational strains of Aβ in heritable and sporadic forms of AD patient samples. We demonstrate that distinct strains of Aβ can be discerned in different disease types, or in different brain compartments within a given patient. Our findings may potentially explain the spectrum of clinical and pathologic features observed in AD.
Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ 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 Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ 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 Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.
↵1C.C., T.L., and J.S. contributed equally to this work.
Author contributions: C.C., T.L., J.S., W.F.D., and S.B.P. designed research; C.C., J.S., M.N., Y.W., A.M.M., C.D.C., and A.O. performed research; J.C.W. and K.G. contributed new reagents/analytic tools; C.D.K., T.D.B., S.G.v.D., L.L., M.I., and C.G. provided human brain samples; C.C., T.L., J.S., M.N., Y.W., W.F.D., and S.B.P. analyzed data; and C.C., T.L., J.S., W.F.D., and S.B.P. wrote the paper.
Reviewers: W.C., Rensselaer Polytechnic Institute; and D.M.H., Washington University School of Medicine.
Conflict of interest statement: The Institute for Neurodegenerative Diseases has a research collaboration with Daiichi Sankyo (Tokyo, Japan). S.B.P. is the chair of the Scientific Advisory Board of Alzheon, Inc., which has not contributed financial or any other support to these studies.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1714966115/-/DCSupplemental.
This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
