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A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease
Synapse loss strongly correlates with cognitive decline in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Deficient Wnt signaling contributes to synapse dysfunction and loss in AD. Consistently, a variant of the LRP6 receptor, (LRP6-Val), with reduced Wnt signaling, i...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624429/ https://www.ncbi.nlm.nih.gov/pubmed/36638182 http://dx.doi.org/10.1126/sciadv.abo7421 |
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author | Jones, Megan E. Büchler, Johanna Dufor, Tom Palomer, Ernest Teo, Samuel Martin-Flores, Nuria Boroviak, Katharina Metzakopian, Emmanouil Gibb, Alasdair Salinas, Patricia C. |
author_facet | Jones, Megan E. Büchler, Johanna Dufor, Tom Palomer, Ernest Teo, Samuel Martin-Flores, Nuria Boroviak, Katharina Metzakopian, Emmanouil Gibb, Alasdair Salinas, Patricia C. |
author_sort | Jones, Megan E. |
collection | PubMed |
description | Synapse loss strongly correlates with cognitive decline in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Deficient Wnt signaling contributes to synapse dysfunction and loss in AD. Consistently, a variant of the LRP6 receptor, (LRP6-Val), with reduced Wnt signaling, is linked to late-onset AD. However, the impact of LRP6-Val on the healthy and AD brain has not been examined. Knock-in mice, generated by gene editing, carrying this Lrp6 variant develop normally. However, neurons from Lrp6-val mice do not respond to Wnt7a, a ligand that promotes synaptic assembly through the Frizzled-5 receptor. Wnt7a stimulates the formation of the low-density lipoprotein receptor-related protein 6 (LRP6)–Frizzled-5 complex but not if LRP6-Val is present. Lrp6-val mice exhibit structural and functional synaptic defects that become pronounced with age. Lrp6-val mice present exacerbated synapse loss around plaques when crossed to the NL-G-F AD model. Our findings uncover a previously unidentified role for Lrp6-val in synapse vulnerability during aging and AD. |
format | Online Article Text |
id | pubmed-10624429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-106244292023-11-04 A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease Jones, Megan E. Büchler, Johanna Dufor, Tom Palomer, Ernest Teo, Samuel Martin-Flores, Nuria Boroviak, Katharina Metzakopian, Emmanouil Gibb, Alasdair Salinas, Patricia C. Sci Adv Neuroscience Synapse loss strongly correlates with cognitive decline in Alzheimer’s disease (AD), but the underlying mechanisms are poorly understood. Deficient Wnt signaling contributes to synapse dysfunction and loss in AD. Consistently, a variant of the LRP6 receptor, (LRP6-Val), with reduced Wnt signaling, is linked to late-onset AD. However, the impact of LRP6-Val on the healthy and AD brain has not been examined. Knock-in mice, generated by gene editing, carrying this Lrp6 variant develop normally. However, neurons from Lrp6-val mice do not respond to Wnt7a, a ligand that promotes synaptic assembly through the Frizzled-5 receptor. Wnt7a stimulates the formation of the low-density lipoprotein receptor-related protein 6 (LRP6)–Frizzled-5 complex but not if LRP6-Val is present. Lrp6-val mice exhibit structural and functional synaptic defects that become pronounced with age. Lrp6-val mice present exacerbated synapse loss around plaques when crossed to the NL-G-F AD model. Our findings uncover a previously unidentified role for Lrp6-val in synapse vulnerability during aging and AD. American Association for the Advancement of Science 2023-01-13 /pmc/articles/PMC10624429/ /pubmed/36638182 http://dx.doi.org/10.1126/sciadv.abo7421 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Neuroscience Jones, Megan E. Büchler, Johanna Dufor, Tom Palomer, Ernest Teo, Samuel Martin-Flores, Nuria Boroviak, Katharina Metzakopian, Emmanouil Gibb, Alasdair Salinas, Patricia C. A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title_full | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title_fullStr | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title_full_unstemmed | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title_short | A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during aging and in Alzheimer’s disease |
title_sort | genetic variant of the wnt receptor lrp6 accelerates synapse degeneration during aging and in alzheimer’s disease |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10624429/ https://www.ncbi.nlm.nih.gov/pubmed/36638182 http://dx.doi.org/10.1126/sciadv.abo7421 |
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