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)

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 > School of Psychology & Neuroscience
• 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