NPTX2 and cognitive dysfunction in Alzheimer’s Disease

Mei-Fang Xiao(Johns Hopkins University), Desheng Xu(Johns Hopkins University), Michael T. Craig(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Kenneth A. Pelkey(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Chun-Che Chien(Johns Hopkins University), Yang Shi(Johns Hopkins University), Juhong Zhang(Johns Hopkins University), Susan M. Resnick(Institute on Aging), Olga Pletniková(Johns Hopkins University), David P. Salmon(University of California San Diego Medical Center), James B. Brewer(University of California San Diego Medical Center), Steven D. Edland(University of California San Diego), Jerzy Węgiel, Benjamin Tycko(Columbia University), Alena Savonenko(Johns Hopkins University), Roger H. Reeves(Johns Hopkins University), Juan C. Troncoso(Johns Hopkins University), Chris J. McBain(Eunice Kennedy Shriver National Institute of Child Health and Human Development), Douglas Galasko(University of California San Diego Medical Center), Paul F. Worley(Johns Hopkins University)
eLife
March 23, 2017
10.7554/elife.23798
Cited by 324Open Access
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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.

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