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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...

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Autores principales: Jones, Megan E., Büchler, Johanna, Dufor, Tom, Palomer, Ernest, Teo, Samuel, Martin-Flores, Nuria, Boroviak, Katharina, Metzakopian, Emmanouil, Gibb, Alasdair, Salinas, Patricia C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
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.
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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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