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Sökning: onr:"swepub:oai:DiVA.org:uu-343799" > Structural heteroge...

Structural heterogeneity and intersubject variability of A beta in familial and sporadic Alzheimer's disease

Condello, Carlo (författare)
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.
Lemmin, Thomas (författare)
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
Stöhr, Jan (författare)
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.
visa fler...
Nick, Mimi (författare)
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
Wu, Yibing (författare)
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
Maxwell, Alison M. (författare)
Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
Watts, Joel C. (författare)
Univ Toronto, Tanz Ctr Res Neurodegenerat Dis, Dept Biochem, Toronto, ON MST 258, Canada.
Caro, Christoffer D. (författare)
Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.
Oehler, Abby (författare)
Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.
Keene, C. Dirk (författare)
Univ Washington, Dept Pathol, Seattle, WA 98195 USA.
Bird, Thomas D. (författare)
VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA.;Univ Washington, Dept Neurol, Seattle, WA 98195 USA.
van Duinen, Sjoerd G. (författare)
Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZA Leiden, Netherlands.
Lannfelt, Lars (författare)
Uppsala universitet,Geriatrik
Ingelsson, Martin (författare)
Uppsala universitet,Geriatrik
Graff, Caroline (författare)
Karolinska Inst, Div Neurogeriatr, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, S-14157 Huddinge, Sweden.;Karolinska Univ Hosp Huddinge, Dept Geriatr Med, S-14186 Stockholm, Sweden.
Giles, Kurt (författare)
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.
DeGrado, William F. (författare)
Univ Calif San Francisco, Weill Inst Neurosci, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Cardiovasc Res Inst, Dept Pharmaceut Chem, San Francisco, CA 94158 USA.
Prusiner, Stanley B. (författare)
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, Dept Biochem & Biophys, San Francisco, CA 94158 USA.
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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. (creator_code:org_t)
NATL ACAD SCIENCES, 2018
2018
Engelska.
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 115:4, s. E782-E791
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Nyckelord

Alzheimer's disease
amyloid-beta
conformational strains
spectral imaging
protein misfolding

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