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Structural heterogeneity and intersubject variability of Aß in familial and sporadic Alzheimer's disease.
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan; Nick, Mimi; Wu, Yibing; Maxwell, Alison M; Watts, Joel C; Caro, Christoffer D; Oehler, Abby; Keene, C Dirk; Bird, Thomas D; van Duinen, Sjoerd G; Lannfelt, Lars; Ingelsson, Martin; Graff, Caroline; Giles, Kurt; DeGrado, William F; Prusiner, Stanley B.
Afiliación
  • Condello C; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • Lemmin T; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • Stöhr J; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
  • Nick M; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • Wu Y; Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • Maxwell AM; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
  • Watts JC; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
  • Caro CD; Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
  • Oehler A; Department of Biochemistry, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON MST 258, Canada.
  • Keene CD; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • Bird TD; Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
  • van Duinen SG; Department of Pathology, University of Washington, Seattle, WA 98195.
  • Lannfelt L; Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108.
  • Ingelsson M; Department of Neurology, University of Washington, Seattle, WA 98195.
  • Graff C; Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
  • Giles K; Molecular Geriatrics, Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
  • DeGrado WF; Molecular Geriatrics, Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
  • Prusiner SB; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
Proc Natl Acad Sci U S A ; 115(4): E782-E791, 2018 01 23.
Article en En | MEDLINE | ID: mdl-29311311
Point mutations in the amyloid-ß (Aß) coding region produce a combination of mutant and WT Aß 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 Aß determines WT Aß conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aß 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 Aß, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aß40 fibrils into transgenic mice expressing only WT Aß induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aß40 prions induce a conformation of WT Aß similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aß prion conformations, which kinetically dominate the spread of prions in the brain.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Conformación Proteica / Péptidos beta-Amiloides / Pliegue de Proteína / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Conformación Proteica / Péptidos beta-Amiloides / Pliegue de Proteína / Enfermedad de Alzheimer Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos