The soluble extracellular fragment of neuroligin-1 targets Aβ oligomers to the postsynaptic region of excitatory synapses.
Amyloid-β oligomers (Aβo) play a major role in the synaptic dysfunction of Alzheimer's disease (AD). Neuroligins are postsynaptic cell-adhesion molecules, that share an extracellular domain with high degree of similarity to acetylcholinesterase (AChE), one of the first putative Aβo receptors. We recently found that Aβo interact with the soluble N-terminal fragment of neuroligin-1 (NL-1). We report here that Aβo associate with NL-1 at excitatory hippocampal synapses, whereas almost no association was observed with neuroligin-2, an isoform present at inhibitory synapses. Studies using purified hippocampal postsynaptic densities indicate that NL-1 interacts with Aβo in a complex with GluN2B-containing NMDA receptors. Additionally, the soluble fragment of NL-1 was used as a scavenger for Aβo. Field excitatory postsynaptic potentials indicate that fragments of NL-1 protect hippocampal neurons from the impairment induced by Aβo. To our knowledge, this is the first report of the interaction between this extracellular fragment of NL-1 and Aβo, strongly suggest that NL-1 facilitates the targeting of Aβo to the postsynaptic regions of excitatory synapses.
Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
Margarita C
MC
Dinamarca
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Monica
M
Di Luca
Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
Juan A
JA
Godoy
Center for Aging and Regeneration (CARE), Department of Cell and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile; Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia; Centro UC Síndrome de Down, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. Electronic address: ninestrosa@bio.puc.cl.
Nibaldo C
NC
Inestrosa
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012995:Solubility; D013569:Synapses / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D016194:Receptors, N-Methyl-D-Aspartate; C093438:neuroligin 1
Aβ oligomer; Excitatory synapses; Hippocampal neurons; Neuroligin-1