Pyk2 overexpression in postsynaptic neurons blocks amyloid β1-42-induced synaptotoxicity in microfluidic co-cultures

Kilinc, Devrim; Vreulx, Anaїs-Camille; Mendes, Tiago; Flaig, Amandine; Coelho, Diego Marques; Verschoore, Maxime; Demiautte, Florie; Amouyel, Philippe; Eysert, Fanny; Dourlen, Pierre; Chapuis, Julien; Costa, Marcos Romualdo; Malmanche, Nicolas; Checler, Frédéric; Lambert, Jean-Charles

Pyk2 overexpression in postsynaptic neurons blocks amyloid β1-42-induced synaptotoxicity in microfluidic co-cultures

Página do item simplificado Estatísticas

dc.contributor.author	Kilinc, Devrim
dc.contributor.author	Vreulx, Anaїs-Camille
dc.contributor.author	Mendes, Tiago
dc.contributor.author	Flaig, Amandine
dc.contributor.author	Coelho, Diego Marques
dc.contributor.author	Verschoore, Maxime
dc.contributor.author	Demiautte, Florie
dc.contributor.author	Amouyel, Philippe
dc.contributor.author	Eysert, Fanny
dc.contributor.author	Dourlen, Pierre
dc.contributor.author	Chapuis, Julien
dc.contributor.author	Costa, Marcos Romualdo
dc.contributor.author	Malmanche, Nicolas
dc.contributor.author	Checler, Frédéric
dc.contributor.author	Lambert, Jean-Charles
dc.date.accessioned	2020-09-01T13:35:55Z
dc.date.available	2020-09-01T13:35:55Z
dc.date.issued	2020-08-28
dc.description.resumo	Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this paper, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1-42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta (Pyk2) –an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels– selectively in postsynaptic neurons is protective against amyloid β1-42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically-relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments	pt_BR
dc.identifier.citation	KILINC, Devrim et al. Pyk2 overexpression in postsynaptic neurons blocks amyloid β1-42-induced synaptotoxicity in microfluidic co-cultures. Brain Communications, [S.l.], fcaa139, ago. 2020. http://dx.doi.org/10.1093/braincomms/fcaa139. Disponível em: https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcaa139/5898625. Acesso em: 1 set. 2020.	pt_BR
dc.identifier.doi	10.1093/braincomms/fcaa139
dc.identifier.uri	https://repositorio.ufrn.br/jspui/handle/123456789/29915
dc.language	en	pt_BR
dc.publisher	Oxford University Press	pt_BR
dc.rights	Attribution-NonCommercial 3.0 Brazil	*
dc.rights.uri	http://creativecommons.org/licenses/by-nc/3.0/br/	*
dc.subject	Alzheimer disease	pt_BR
dc.subject	Synapses	pt_BR
dc.subject	Microfluidics	pt_BR
dc.subject	Coculture techniques	pt_BR
dc.subject	Amyloid beta-peptides	pt_BR
dc.subject	Amyloid beta-protein precursor	pt_BR
dc.title	Pyk2 overexpression in postsynaptic neurons blocks amyloid β1-42-induced synaptotoxicity in microfluidic co-cultures	pt_BR
dc.type	article	pt_BR