Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission

Abstract The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer’s disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by lo...

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Autores principales:	Anna Kreis, Jana Desloovere, Nuria Suelves, Nathalie Pierrot, Xavier Yerna, Farah Issa, Olivier Schakman, Roberta Gualdani, Marie de Clippele, Nicolas Tajeddine, Pascal Kienlen-Campard, Robrecht Raedt, Jean-Noël Octave, Philippe Gailly
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8573bf1d0f514383a0caa67d43212752
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spelling	oai:doaj.org-article:8573bf1d0f514383a0caa67d432127522021-12-02T19:09:20ZOverexpression of wild-type human amyloid precursor protein alters GABAergic transmission10.1038/s41598-021-97144-32045-2322https://doaj.org/article/8573bf1d0f514383a0caa67d432127522021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97144-3https://doaj.org/toc/2045-2322Abstract The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer’s disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABAB receptors (GABABRs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPPwt) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aβ. hAPPwt mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPPwt did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABABRs and subsequently reducing GABA release. By using a specific presynaptic GABABR antagonist, we were able to rescue hyperexcitation in hAPPwt animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.Anna KreisJana DesloovereNuria SuelvesNathalie PierrotXavier YernaFarah IssaOlivier SchakmanRoberta GualdaniMarie de ClippeleNicolas TajeddinePascal Kienlen-CampardRobrecht RaedtJean-Noël OctavePhilippe GaillyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna Kreis Jana Desloovere Nuria Suelves Nathalie Pierrot Xavier Yerna Farah Issa Olivier Schakman Roberta Gualdani Marie de Clippele Nicolas Tajeddine Pascal Kienlen-Campard Robrecht Raedt Jean-Noël Octave Philippe Gailly Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
description	Abstract The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer’s disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABAB receptors (GABABRs), subsequently decreasing the probability of neurotransmitter release. In this body of work, we were able to show that overexpression of wild-type human APP in mice (hAPPwt) causes early cognitive impairment, neuronal loss, and electrophysiological abnormalities in the absence of amyloid plaques and at very low levels of Aβ. hAPPwt mice exhibited neuronal overexcitation that was evident in EEG and increased long-term potentiation (LTP). Overexpression of hAPPwt did not alter GABAergic/glutamatergic receptor components or GABA production ability. Nonetheless, we detected a decrease of GABA but not glutamate that could be linked to soluble APP fragments, acting on presynaptic GABABRs and subsequently reducing GABA release. By using a specific presynaptic GABABR antagonist, we were able to rescue hyperexcitation in hAPPwt animals. Our results provide evidence that APP plays a crucial role in regulating inhibitory neurotransmission.
format	article
author	Anna Kreis Jana Desloovere Nuria Suelves Nathalie Pierrot Xavier Yerna Farah Issa Olivier Schakman Roberta Gualdani Marie de Clippele Nicolas Tajeddine Pascal Kienlen-Campard Robrecht Raedt Jean-Noël Octave Philippe Gailly
author_facet	Anna Kreis Jana Desloovere Nuria Suelves Nathalie Pierrot Xavier Yerna Farah Issa Olivier Schakman Roberta Gualdani Marie de Clippele Nicolas Tajeddine Pascal Kienlen-Campard Robrecht Raedt Jean-Noël Octave Philippe Gailly
author_sort	Anna Kreis
title	Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
title_short	Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
title_full	Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
title_fullStr	Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
title_full_unstemmed	Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission
title_sort	overexpression of wild-type human amyloid precursor protein alters gabaergic transmission
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/8573bf1d0f514383a0caa67d43212752
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Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission

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