uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Structural heterogeneity and intersubject variability of A beta in familial and sporadic Alzheimer's disease
Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA..
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA 94158 USA..
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA..
Show others and affiliations
2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 4, p. E782-E791Article in journal (Refereed) Published
Abstract [en]

Point mutations in the amyloid-beta (A beta) coding region produce a combination of mutant and WT A beta 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 A beta determines WT A beta conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of A beta 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 A beta, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant A beta 40 fibrils into transgenic mice expressing only WT A beta induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant A beta 40 prions induce a conformation of WT A beta similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial A beta prion conformations, which kinetically dominate the spread of prions in the brain.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2018. Vol. 115, no 4, p. E782-E791
Keywords [en]
Alzheimer's disease, amyloid-beta, conformational strains, spectral imaging, protein misfolding
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-343799DOI: 10.1073/pnas.1714966115ISI: 000423097800028PubMedID: 29311311OAI: oai:DiVA.org:uu-343799DiVA, id: diva2:1187427
Funder
Stockholm County CouncilAvailable from: 2018-03-05 Created: 2018-03-05 Last updated: 2018-03-05Bibliographically approved

Open Access in DiVA

fulltext(2716 kB)54 downloads
File information
File name FULLTEXT01.pdfFile size 2716 kBChecksum SHA-512
2ec964a58566c62bd01dce1084ff71e5bc55ab4d8391a842c68050b343cb8402d8821d82120e8ecc7410dbf8196d89a6ada18b42b6172b03caa7ee53e3a34bf2
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Lannfelt, LarsIngelsson, Martin

Search in DiVA

By author/editor
Lannfelt, LarsIngelsson, Martin
By organisation
Geriatrics
In the same journal
Proceedings of the National Academy of Sciences of the United States of America
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 54 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 117 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf