NPTX2 and cognitive dysfunction in Alzheimer's Disease

• Published in: eLife Vol. 6
• Main Authors: Xiao, Mei-Fang, Xu, Desheng, Craig, Michael T, Pelkey, Kenneth A, Chien, Chun-Che, Shi, Yang, Zhang, Juhong, Resnick, Susan, Pletnikova, Olga, Salmon, David, Brewer, James, Edland, Steven, Wegiel, Jerzy, Tycko, Benjamin, Savonenko, Alena, Reeves, Roger H, Troncoso, Juan C, McBain, Chris J, Galasko, Douglas, Worley, Paul F
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 23-03-2017; eLife Sciences Publications, Ltd
• Subjects: Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloidosis; Animals; Brain research; C-Reactive Protein - analysis; C-Reactive Protein - cerebrospinal fluid; Cerebral Cortex - pathology; Cerebrospinal fluid; Cognitive ability; Cognitive Dysfunction - physiopathology; Dementia; Disease Models, Animal; Excitability; Firing pattern; Hippocampus; Hippocampus - pathology; Human subjects; Humans; immediate early gene; inhibitory neuron; Interneurons; Medicine; Memory; Mice; Mice, Knockout; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - cerebrospinal fluid; Neurodegeneration; Neurodegenerative diseases; Neuroscience; Neurosciences; Parvalbumin; Pyramidal cells; Rodents; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; United States > US; California; alzheimer’s disease; mmediate early gene; neuroscience; inhibitory neuron; dementia; immediate early gene; Alzheimer's disease
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.23798

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,
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.