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Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Dec 05; Vol. 114 (49), pp. 13018-13023. Date of Electronic Publication: 2017 Nov 20. - Publication Year :
- 2017
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Abstract
- The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Alzheimer Disease classification
Alzheimer Disease genetics
Alzheimer Disease pathology
Amyloid classification
Amyloid ultrastructure
Amyloid beta-Peptides metabolism
Amyloid beta-Protein Precursor genetics
Amyloid beta-Protein Precursor metabolism
Animals
Disease Models, Animal
Female
Fluorescent Dyes chemistry
Frontal Lobe chemistry
Frontal Lobe metabolism
Frontal Lobe pathology
Gene Expression
Humans
Male
Mice
Occipital Lobe chemistry
Occipital Lobe metabolism
Occipital Lobe pathology
Peptide Hydrolases chemistry
Plaque, Amyloid classification
Plaque, Amyloid genetics
Plaque, Amyloid pathology
Presenilin-1 genetics
Presenilin-1 metabolism
Protein Binding
Protein Conformation
Proteolysis
Spectrometry, Fluorescence
Temporal Lobe chemistry
Temporal Lobe metabolism
Temporal Lobe pathology
Thiophenes chemistry
Alzheimer Disease metabolism
Amyloid chemistry
Amyloid beta-Peptides chemistry
Plaque, Amyloid metabolism
Protein Aggregates
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 49
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 29158413
- Full Text :
- https://doi.org/10.1073/pnas.1713215114