Cargando…

Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events

Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly...

Descripción completa

Detalles Bibliográficos
Autores principales: Brown, Carolyn Nicole, Rumian, Nicole L., Tullis, Jonathan E., Coultrap, Steven J., Bayer, K. Ulrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127195/
https://www.ncbi.nlm.nih.gov/pubmed/35620430
http://dx.doi.org/10.1016/j.isci.2022.104368
_version_ 1784712296816181248
author Brown, Carolyn Nicole
Rumian, Nicole L.
Tullis, Jonathan E.
Coultrap, Steven J.
Bayer, K. Ulrich
author_facet Brown, Carolyn Nicole
Rumian, Nicole L.
Tullis, Jonathan E.
Coultrap, Steven J.
Bayer, K. Ulrich
author_sort Brown, Carolyn Nicole
collection PubMed
description Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding. However, our study did not find any evidence for direct effects of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activity in vitro. Most importantly, in neurons, the Aβ-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct Aβ binding. Together, our results indicate that synaptic Aβ effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events.
format Online
Article
Text
id pubmed-9127195
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-91271952022-05-25 Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events Brown, Carolyn Nicole Rumian, Nicole L. Tullis, Jonathan E. Coultrap, Steven J. Bayer, K. Ulrich iScience Article Aβ bears homology to the CaMKII regulatory domain, and peptides derived from this domain can bind and disrupt the CaMKII holoenzyme, suggesting that Aβ could have a similar effect. Notably, Aβ impairs the synaptic CaMKII accumulation that is mediated by GluN2B binding, which requires CaMKII assembly into holoenzymes. Furthermore, this Aβ-induced impairment is prevented by CaMKII inhibitors that should also inhibit the putative direct Aβ binding. However, our study did not find any evidence for direct effects of Aβ on CaMKII: Aβ did not directly disrupt CaMKII holoenzymes, GluN2B binding, T286 autophosphorylation, or kinase activity in vitro. Most importantly, in neurons, the Aβ-induced impairment of CaMKII synaptic accumulation was prevented by an ATP-competitive CaMKII inhibitor that would not interfere with the putative direct Aβ binding. Together, our results indicate that synaptic Aβ effects are not mediated by direct binding to CaMKII, but instead require CaMKII activation via indirect signaling events. Elsevier 2022-05-06 /pmc/articles/PMC9127195/ /pubmed/35620430 http://dx.doi.org/10.1016/j.isci.2022.104368 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Brown, Carolyn Nicole
Rumian, Nicole L.
Tullis, Jonathan E.
Coultrap, Steven J.
Bayer, K. Ulrich
Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title_full Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title_fullStr Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title_full_unstemmed Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title_short Aβ-induced synaptic impairments require CaMKII activity that is stimulated by indirect signaling events
title_sort aβ-induced synaptic impairments require camkii activity that is stimulated by indirect signaling events
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9127195/
https://www.ncbi.nlm.nih.gov/pubmed/35620430
http://dx.doi.org/10.1016/j.isci.2022.104368
work_keys_str_mv AT browncarolynnicole abinducedsynapticimpairmentsrequirecamkiiactivitythatisstimulatedbyindirectsignalingevents
AT rumiannicolel abinducedsynapticimpairmentsrequirecamkiiactivitythatisstimulatedbyindirectsignalingevents
AT tullisjonathane abinducedsynapticimpairmentsrequirecamkiiactivitythatisstimulatedbyindirectsignalingevents
AT coultrapstevenj abinducedsynapticimpairmentsrequirecamkiiactivitythatisstimulatedbyindirectsignalingevents
AT bayerkulrich abinducedsynapticimpairmentsrequirecamkiiactivitythatisstimulatedbyindirectsignalingevents