The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression

Abstract The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant ph...

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Autores principales:	Maa O. Quartey, Jennifer N. K. Nyarko, Jason M. Maley, Jocelyn R. Barnes, Maria A. C. Bolanos, Ryan M. Heistad, Kaeli J. Knudsen, Paul R. Pennington, Josef Buttigieg, Carlos E. De Carvalho, Scot C. Leary, Matthew P. Parsons, Darrell D. Mousseau
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/986c73bc802940a9ae4cdf2d043e1a43
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spelling	oai:doaj.org-article:986c73bc802940a9ae4cdf2d043e1a432021-12-02T14:12:41ZThe Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression10.1038/s41598-020-80164-w2045-2322https://doaj.org/article/986c73bc802940a9ae4cdf2d043e1a432021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80164-whttps://doaj.org/toc/2045-2322Abstract The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1–38) interacts differently with Aβ(1–40) and Aβ(1–42) and, in general, Aβ(1–38) interferes with the conversion of Aβ(1–42) to a β-sheet-rich aggregate. Functionally, Aβ(1–38) reverses the negative impact of Aβ(1–42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1–42) phenotype in Caenorhabditis elegans. Aβ(1–38) also reverses any loss of MTT conversion induced by Aβ(1–40) and Aβ(1–42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1–38) and Aβ(1–42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1–42)/Aβ(1–38) [and Aβ(1–42)/Aβ(1–40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1–38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1–42).Maa O. QuarteyJennifer N. K. NyarkoJason M. MaleyJocelyn R. BarnesMaria A. C. BolanosRyan M. HeistadKaeli J. KnudsenPaul R. PenningtonJosef ButtigiegCarlos E. De CarvalhoScot C. LearyMatthew P. ParsonsDarrell D. MousseauNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maa O. Quartey Jennifer N. K. Nyarko Jason M. Maley Jocelyn R. Barnes Maria A. C. Bolanos Ryan M. Heistad Kaeli J. Knudsen Paul R. Pennington Josef Buttigieg Carlos E. De Carvalho Scot C. Leary Matthew P. Parsons Darrell D. Mousseau The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
description	Abstract The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that Aβ(1–38) interacts differently with Aβ(1–40) and Aβ(1–42) and, in general, Aβ(1–38) interferes with the conversion of Aβ(1–42) to a β-sheet-rich aggregate. Functionally, Aβ(1–38) reverses the negative impact of Aβ(1–42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an Aβ(1–42) phenotype in Caenorhabditis elegans. Aβ(1–38) also reverses any loss of MTT conversion induced by Aβ(1–40) and Aβ(1–42) in HT-22 hippocampal neurons and APOE ε4-positive human fibroblasts, although the combination of Aβ(1–38) and Aβ(1–42) inhibits MTT conversion in APOE ε4-negative fibroblasts. A greater ratio of soluble Aβ(1–42)/Aβ(1–38) [and Aβ(1–42)/Aβ(1–40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that Aβ(1–38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant Aβ(1–42).
format	article
author	Maa O. Quartey Jennifer N. K. Nyarko Jason M. Maley Jocelyn R. Barnes Maria A. C. Bolanos Ryan M. Heistad Kaeli J. Knudsen Paul R. Pennington Josef Buttigieg Carlos E. De Carvalho Scot C. Leary Matthew P. Parsons Darrell D. Mousseau
author_facet	Maa O. Quartey Jennifer N. K. Nyarko Jason M. Maley Jocelyn R. Barnes Maria A. C. Bolanos Ryan M. Heistad Kaeli J. Knudsen Paul R. Pennington Josef Buttigieg Carlos E. De Carvalho Scot C. Leary Matthew P. Parsons Darrell D. Mousseau
author_sort	Maa O. Quartey
title	The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
title_short	The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
title_full	The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
title_fullStr	The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
title_full_unstemmed	The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression
title_sort	aβ(1–38) peptide is a negative regulator of the aβ(1–42) peptide implicated in alzheimer disease progression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/986c73bc802940a9ae4cdf2d043e1a43
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The Aβ(1–38) peptide is a negative regulator of the Aβ(1–42) peptide implicated in Alzheimer disease progression

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