NPTX2 and cognitive dysfunction in Alzheimer’s disease

Xiao, M.-F. et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer’s disease. eLife, 6, e23798. (doi: 10.7554/eLife.23798) (PMID:28440221) (PMCID:PMC5404919)

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Abstract

Memory loss in Alzheimer’s disease (AD) is attributed to pervasive weakening and loss of synapses. Here, we present findings supporting a special role for excitatory synapses connecting pyramidal neurons of the hippocampus and cortex with fast-spiking parvalbumin (PV) interneurons that control network excitability and rhythmicity. Excitatory synapses on PV interneurons are dependent on the AMPA receptor subunit GluA4, which is regulated by presynaptic expression of the synaptogenic immediate early gene NPTX2 by pyramidal neurons. In a mouse model of AD amyloidosis, Nptx2-/- results in reduced GluA4 expression, disrupted rhythmicity, and increased pyramidal neuron excitability. Postmortem human AD cortex shows profound reductions of NPTX2 and coordinate reductions of GluA4. NPTX2 in human CSF is reduced in subjects with AD and shows robust correlations with cognitive performance and hippocampal volume. These findings implicate failure of adaptive control of pyramidal neuron-PV circuits as a pathophysiological mechanism contributing to cognitive failure in AD.

Item Type:Articles
Additional Information:This study was supported by NIMH MH100024 (PFW), (R35 NS-097966) (PFW), P50 AG005146-27 (PFW, JCT), Down Syndrome Research and Treatment Foundation and Research Down Syndrome (MX and RR), NIA AG05131 (DS, SE, DG), Alzheimer’s Disease Drug Discovery Foundation (DX, DG) and in part by the Intramural Research Program, National Institute on Aging, and National Institutes on Child Health and Development, NIH.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Craig, Dr Mick
Authors: Xiao, M.-F., Xu, D., Craig, M. T., Pelkey, K. A., Chien, C.-C., Shi, Y., Zhang, J., Resnick, S., Pletnikova, O., Salmon, D., Brewer, J., Edland, S., Wegiel, J., Tycko, B., Savonenko, A., Reeves, R. H., Troncoso, J. C., McBain, C. J., Galasko, D., and Worley, P. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Copyright Holders:Copyright © 2017 Xiao et al.
First Published:First published in eLife 6: e23798
Publisher Policy:Reproduced under a Creative Commons License

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