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Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease
Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer’s disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorat...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894682/ https://www.ncbi.nlm.nih.gov/pubmed/36260691 http://dx.doi.org/10.1126/scitranslmed.abn9380 |
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author | Zhou, Bo Lu, Jacqueline G. Siddu, Alberto Wernig, Marius Südhof, Thomas C. |
author_facet | Zhou, Bo Lu, Jacqueline G. Siddu, Alberto Wernig, Marius Südhof, Thomas C. |
author_sort | Zhou, Bo |
collection | PubMed |
description | Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer’s disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish–mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations. |
format | Online Article Text |
id | pubmed-9894682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-98946822023-02-02 Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease Zhou, Bo Lu, Jacqueline G. Siddu, Alberto Wernig, Marius Südhof, Thomas C. Sci Transl Med Article Mutations in β-amyloid (Aβ) precursor protein (APP) cause familial Alzheimer’s disease (AD) probably by enhancing Aβ peptides production from APP. An antibody targeting Aβ (aducanumab) was approved as an AD treatment; however, some Aβ antibodies have been reported to accelerate, instead of ameliorating, cognitive decline in individuals with AD. Using conditional APP mutations in human neurons for perfect isogenic controls and translational relevance, we found that the APP-Swedish mutation in familial AD increased synapse numbers and synaptic transmission, whereas the APP deletion decreased synapse numbers and synaptic transmission. Inhibition of BACE1, the protease that initiates Aβ production from APP, lowered synapse numbers, suppressed synaptic transmission in wild-type neurons, and occluded the phenotype of APP-Swedish–mutant neurons. Modest elevations of Aβ, conversely, elevated synapse numbers and synaptic transmission. Thus, the familial AD-linked APP-Swedish mutation under physiologically relevant conditions increased synaptic connectivity in human neurons via a modestly enhanced production of Aβ. These data are consistent with the relative inefficacy of BACE1 and anti-Aβ treatments in AD and the chronic nature of AD pathogenesis, suggesting that AD pathogenesis is not simply caused by overproduction of toxic Aβ but rather by a long-term effect of elevated Aβ concentrations. 2022-10-19 2022-10-19 /pmc/articles/PMC9894682/ /pubmed/36260691 http://dx.doi.org/10.1126/scitranslmed.abn9380 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Zhou, Bo Lu, Jacqueline G. Siddu, Alberto Wernig, Marius Südhof, Thomas C. Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title | Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title_full | Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title_fullStr | Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title_full_unstemmed | Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title_short | Synaptogenic effect of APP-Swedish mutation in familial Alzheimer’s disease |
title_sort | synaptogenic effect of app-swedish mutation in familial alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894682/ https://www.ncbi.nlm.nih.gov/pubmed/36260691 http://dx.doi.org/10.1126/scitranslmed.abn9380 |
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