Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation

Abstract Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s diseas...

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Autores principales:	Nobuto Kakuda, Mako Takami, Masayasu Okochi, Kensaku Kasuga, Yasuo Ihara, Takeshi Ikeuchi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/5f2ce92124e54e15a0a0967af4b57009
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spelling	oai:doaj.org-article:5f2ce92124e54e15a0a0967af4b570092021-11-07T12:17:52ZSwitched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation10.1038/s41398-021-01684-12158-3188https://doaj.org/article/5f2ce92124e54e15a0a0967af4b570092021-11-01T00:00:00Zhttps://doi.org/10.1038/s41398-021-01684-1https://doaj.org/toc/2158-3188Abstract Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.Nobuto KakudaMako TakamiMasayasu OkochiKensaku KasugaYasuo IharaTakeshi IkeuchiNature Publishing GrouparticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENTranslational Psychiatry, Vol 11, Iss 1, Pp 1-6 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Nobuto Kakuda Mako Takami Masayasu Okochi Kensaku Kasuga Yasuo Ihara Takeshi Ikeuchi Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
description	Abstract Presenilin (PS) with a genetic mutation generates abundant β-amyloid protein (Aβ) 43. Senile plaques are formed by Aβ43 in the cerebral parenchyma together with Aβ42 at middle ages. These brains cause the early onset of Alzheimer’s disease (AD), which is known as familial Alzheimer’s disease (FAD). Based on the stepwise processing model of Aβ generation by γ-secretase, we reassessed the levels of Aβs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aβ38, Aβ40, and Aβ42 were generated in the CSF of FAD participants, the levels of Aβ43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aβ43 was unchanged in FAD participants. These characteristics of Aβ generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aβ38 and Aβ40 generation from their precursors, Aβ42 and Aβ43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aβ38/Aβ42 and Aβ40/Aβ43 in PS1 mutants were lower than those in the WT. However, the ratio of Aβ43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aβ/AICD ratios were decreased or unchanged. Importantly, liquid chromatography–mass spectrometry found that the generation of Aβ43 was stimulated from Aβ48 in PS1 mutants. This result indicates that PS1 mutants switched the Aβ43 generating line, which reflects the level of Aβ43 in the CSF and forming senile plaques.
format	article
author	Nobuto Kakuda Mako Takami Masayasu Okochi Kensaku Kasuga Yasuo Ihara Takeshi Ikeuchi
author_facet	Nobuto Kakuda Mako Takami Masayasu Okochi Kensaku Kasuga Yasuo Ihara Takeshi Ikeuchi
author_sort	Nobuto Kakuda
title	Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
title_short	Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
title_full	Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
title_fullStr	Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
title_full_unstemmed	Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation
title_sort	switched aβ43 generation in familial alzheimer’s disease with presenilin 1 mutation
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/5f2ce92124e54e15a0a0967af4b57009
work_keys_str_mv	AT nobutokakuda switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation AT makotakami switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation AT masayasuokochi switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation AT kensakukasuga switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation AT yasuoihara switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation AT takeshiikeuchi switchedab43generationinfamilialalzheimersdiseasewithpresenilin1mutation
_version_	1718443488945635328

Switched Aβ43 generation in familial Alzheimer’s disease with presenilin 1 mutation

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