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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E782-E791. doi: 10.1073/pnas.1714966115. Epub 2018 Jan 8.

Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.

Author information

1
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
2
Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
3
Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, CA 94158.
4
Department of Biochemistry, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON MST 258, Canada.
5
Department of Pathology, University of Washington, Seattle, WA 98195.
6
Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108.
7
Department of Neurology, University of Washington, Seattle, WA 98195.
8
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
9
Molecular Geriatrics, Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
10
Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
11
Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
12
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158; william.degrado@ucsf.edu stanley.prusiner@ucsf.edu.
13
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; amyloid-β; conformational strains; protein misfolding; spectral imaging

PMID:
29311311
PMCID:
PMC5789926
DOI:
10.1073/pnas.1714966115
[Indexed for MEDLINE]
Free PMC Article

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