Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils

Abstract Alzheimer’s disease is characterized by neuritic plaques, the main protein components of which are β-amyloid (Aβ) peptides deposited as β-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aβ peptides; it usually accompanies Alzheimer’s dis...

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Autores principales:	Kathryn P. Scherpelz, Songlin Wang, Peter Pytel, Rama S. Madhurapantula, Atul K. Srivastava, Joseph R. Sachleben, Joseph Orgel, Yoshitaka Ishii, Stephen C. Meredith
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/549a89f7338448fd9a222cd6a6278088
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spelling	oai:doaj.org-article:549a89f7338448fd9a222cd6a62780882021-12-02T11:45:54ZAtomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils10.1038/s41598-020-80042-52045-2322https://doaj.org/article/549a89f7338448fd9a222cd6a62780882021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80042-5https://doaj.org/toc/2045-2322Abstract Alzheimer’s disease is characterized by neuritic plaques, the main protein components of which are β-amyloid (Aβ) peptides deposited as β-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aβ peptides; it usually accompanies Alzheimer’s disease, though it sometimes occurs in the absence of neuritic plaques, as AD also occurs without accompanying CAA. Although neuritic plaques and vascular deposits have similar protein compositions, one of the characteristic features of amyloids is polymorphism, i.e., the ability of a single pure peptide to adopt multiple conformations in fibrils, depending on fibrillization conditions. For this reason, we asked whether the Aβ fibrils in neuritic plaques differed structurally from those in cerebral blood vessels. To address this question, we used seeding techniques, starting with amyloid-enriched material from either brain parenchyma or cerebral blood vessels (using meninges as the source). These amyloid-enriched preparations were then added to fresh, disaggregated solutions of Aβ to make replicate fibrils, as described elsewhere. Such fibrils were then studied by solid-state NMR, fiber X-ray diffraction, and other biophysical techniques. We observed chemical shift differences between parenchymal vs. vascular-seeded replicate fibrils in select sites (in particular, Ala2, Phe4, Val12, and Gln15 side chains) in two-dimensional 13C-13C correlation solid-state NMR spectra, strongly indicating structural differences at these sites. X-ray diffraction studies also indicated that vascular-seeded fibrils displayed greater order than parenchyma-seeded fibrils in the “side-chain dimension” (~ 10 Å reflection), though the “hydrogen-bond dimensions” (~ 5 Å reflection) were alike. These results indicate that the different nucleation conditions at two sites in the brain, parenchyma and blood vessels, affect the fibril products that get formed at each site, possibly leading to distinct pathophysiological outcomes.Kathryn P. ScherpelzSonglin WangPeter PytelRama S. MadhurapantulaAtul K. SrivastavaJoseph R. SachlebenJoseph OrgelYoshitaka IshiiStephen C. MeredithNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kathryn P. Scherpelz Songlin Wang Peter Pytel Rama S. Madhurapantula Atul K. Srivastava Joseph R. Sachleben Joseph Orgel Yoshitaka Ishii Stephen C. Meredith Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
description	Abstract Alzheimer’s disease is characterized by neuritic plaques, the main protein components of which are β-amyloid (Aβ) peptides deposited as β-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aβ peptides; it usually accompanies Alzheimer’s disease, though it sometimes occurs in the absence of neuritic plaques, as AD also occurs without accompanying CAA. Although neuritic plaques and vascular deposits have similar protein compositions, one of the characteristic features of amyloids is polymorphism, i.e., the ability of a single pure peptide to adopt multiple conformations in fibrils, depending on fibrillization conditions. For this reason, we asked whether the Aβ fibrils in neuritic plaques differed structurally from those in cerebral blood vessels. To address this question, we used seeding techniques, starting with amyloid-enriched material from either brain parenchyma or cerebral blood vessels (using meninges as the source). These amyloid-enriched preparations were then added to fresh, disaggregated solutions of Aβ to make replicate fibrils, as described elsewhere. Such fibrils were then studied by solid-state NMR, fiber X-ray diffraction, and other biophysical techniques. We observed chemical shift differences between parenchymal vs. vascular-seeded replicate fibrils in select sites (in particular, Ala2, Phe4, Val12, and Gln15 side chains) in two-dimensional 13C-13C correlation solid-state NMR spectra, strongly indicating structural differences at these sites. X-ray diffraction studies also indicated that vascular-seeded fibrils displayed greater order than parenchyma-seeded fibrils in the “side-chain dimension” (~ 10 Å reflection), though the “hydrogen-bond dimensions” (~ 5 Å reflection) were alike. These results indicate that the different nucleation conditions at two sites in the brain, parenchyma and blood vessels, affect the fibril products that get formed at each site, possibly leading to distinct pathophysiological outcomes.
format	article
author	Kathryn P. Scherpelz Songlin Wang Peter Pytel Rama S. Madhurapantula Atul K. Srivastava Joseph R. Sachleben Joseph Orgel Yoshitaka Ishii Stephen C. Meredith
author_facet	Kathryn P. Scherpelz Songlin Wang Peter Pytel Rama S. Madhurapantula Atul K. Srivastava Joseph R. Sachleben Joseph Orgel Yoshitaka Ishii Stephen C. Meredith
author_sort	Kathryn P. Scherpelz
title	Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
title_short	Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
title_full	Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
title_fullStr	Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
title_full_unstemmed	Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils
title_sort	atomic-level differences between brain parenchymal- and cerebrovascular-seeded aβ fibrils
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/549a89f7338448fd9a222cd6a6278088
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Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aβ fibrils

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