NPTX2 and cognitive dysfunction in Alzheimer’s Disease
Mei-Fang Xiao,
Desheng Xu,
Michael T Craig,
Kenneth A Pelkey,
Chun-Che Chien,
Yang Shi,
Juhong Zhang,
Susan Resnick,
Olga Pletnikova,
David Salmon,
James Brewer,
Steven Edland,
Jerzy Wegiel,
Benjamin Tycko,
Alena Savonenko,
Roger H Reeves,
Juan C Troncoso,
Chris J McBain,
Douglas Galasko,
Paul F Worley
Affiliations
Mei-Fang Xiao
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Desheng Xu
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, Bethesda, United States
Kenneth A Pelkey
Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, Bethesda, United States
Chun-Che Chien
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Yang Shi
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Juhong Zhang
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Susan Resnick
Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, United States
Olga Pletnikova
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
David Salmon
Department of Neurosciences, University of California San Diego Medical Center, San Diego, United States; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego Medical Center, San Diego, United States
James Brewer
Department of Neurosciences, University of California San Diego Medical Center, San Diego, United States; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego Medical Center, San Diego, United States
Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego Medical Center, San Diego, United States; Division of Biostatistics and Bioinformatics, University of California San Diego, San Diego, United States
Jerzy Wegiel
Institute for Basic Research, New York City, United States
Benjamin Tycko
Taub Institute for Research on Alzheimer’s disease and the Aging Brain, Columbia University, New York City, United States
Alena Savonenko
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States
Roger H Reeves
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Juan C Troncoso
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
Chris J McBain
Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, Bethesda, United States
Douglas Galasko
Department of Neurosciences, University of California San Diego Medical Center, San Diego, United States; Shiley-Marcos Alzheimer's Disease Research Center, University of California San Diego Medical Center, San Diego, United States
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States
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.
