Cargando…

Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease

Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms medi...

Descripción completa

Detalles Bibliográficos
Autores principales: Ortiz-Sanz, Carolina, Balantzategi, Uxue, Quintela-López, Tania, Ruiz, Asier, Luchena, Celia, Zuazo-Ibarra, Jone, Capetillo-Zarate, Estibaliz, Matute, Carlos, Zugaza, José L., Alberdi, Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934345/
https://www.ncbi.nlm.nih.gov/pubmed/35306512
http://dx.doi.org/10.1038/s41419-022-04687-y
_version_ 1784671828889829376
author Ortiz-Sanz, Carolina
Balantzategi, Uxue
Quintela-López, Tania
Ruiz, Asier
Luchena, Celia
Zuazo-Ibarra, Jone
Capetillo-Zarate, Estibaliz
Matute, Carlos
Zugaza, José L.
Alberdi, Elena
author_facet Ortiz-Sanz, Carolina
Balantzategi, Uxue
Quintela-López, Tania
Ruiz, Asier
Luchena, Celia
Zuazo-Ibarra, Jone
Capetillo-Zarate, Estibaliz
Matute, Carlos
Zugaza, José L.
Alberdi, Elena
author_sort Ortiz-Sanz, Carolina
collection PubMed
description Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with Aβ(42) load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice. Importantly, NR2B and PSD95 dysregulation was revealed by an increased expression of both proteins in Aβ-injected mouse hippocampi. In cultured neurons, Aβ oligomers increased the NR2B-containing NMDAR density in neuronal membranes and the NMDA-induced intracellular Ca(2+) increase, in addition to colocalization in dendrites of NR2B subunit and PSD95. Mechanistically, Aβ oligomers required integrin β1 to promote synaptic location and function of NR2B-containing NMDARs and PSD95 by phosphorylation through classic PKCs. These results provide evidence that Aβ oligomers modify the contribution of NR2B to NMDAR composition and function in the early stages of AD through an integrin β1 and PKC-dependent pathway. These data reveal a novel role of Aβ oligomers in synaptic dysfunction that may be relevant to early-stage AD pathogenesis.
format Online
Article
Text
id pubmed-8934345
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-89343452022-04-01 Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease Ortiz-Sanz, Carolina Balantzategi, Uxue Quintela-López, Tania Ruiz, Asier Luchena, Celia Zuazo-Ibarra, Jone Capetillo-Zarate, Estibaliz Matute, Carlos Zugaza, José L. Alberdi, Elena Cell Death Dis Article Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with Aβ(42) load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice. Importantly, NR2B and PSD95 dysregulation was revealed by an increased expression of both proteins in Aβ-injected mouse hippocampi. In cultured neurons, Aβ oligomers increased the NR2B-containing NMDAR density in neuronal membranes and the NMDA-induced intracellular Ca(2+) increase, in addition to colocalization in dendrites of NR2B subunit and PSD95. Mechanistically, Aβ oligomers required integrin β1 to promote synaptic location and function of NR2B-containing NMDARs and PSD95 by phosphorylation through classic PKCs. These results provide evidence that Aβ oligomers modify the contribution of NR2B to NMDAR composition and function in the early stages of AD through an integrin β1 and PKC-dependent pathway. These data reveal a novel role of Aβ oligomers in synaptic dysfunction that may be relevant to early-stage AD pathogenesis. Nature Publishing Group UK 2022-03-19 /pmc/articles/PMC8934345/ /pubmed/35306512 http://dx.doi.org/10.1038/s41419-022-04687-y Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ortiz-Sanz, Carolina
Balantzategi, Uxue
Quintela-López, Tania
Ruiz, Asier
Luchena, Celia
Zuazo-Ibarra, Jone
Capetillo-Zarate, Estibaliz
Matute, Carlos
Zugaza, José L.
Alberdi, Elena
Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title_full Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title_fullStr Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title_full_unstemmed Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title_short Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease
title_sort amyloid β / pkc-dependent alterations in nmda receptor composition are detected in early stages of alzheimer´s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934345/
https://www.ncbi.nlm.nih.gov/pubmed/35306512
http://dx.doi.org/10.1038/s41419-022-04687-y
work_keys_str_mv AT ortizsanzcarolina amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT balantzategiuxue amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT quintelalopeztania amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT ruizasier amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT luchenacelia amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT zuazoibarrajone amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT capetillozarateestibaliz amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT matutecarlos amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT zugazajosel amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease
AT alberdielena amyloidbpkcdependentalterationsinnmdareceptorcompositionaredetectedinearlystagesofalzheimersdisease