Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A
Weiwei Zhong, Anika Wu, Ken Berglund, Xiaohuan Gu, Michael Q. Jiang, Jay Talati, Jingjie Zhao, Ling Wei, Shan Ping Yu
Abstract
Abstract The Ca 2+ hypothesis for Alzheimer's disease (AD) conceives Ca 2+ dyshomeostasis as a common mechanism of AD; the cause of Ca 2+ dysregulation, however, is obscure. Meanwhile, hyperactivities of N‐Methyl‐D‐aspartate receptors (NMDARs), the primary mediator of Ca 2+ influx, are reported in AD. GluN3A (NR3A) is an NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for sustained Ca 2+ homeostasis and its deficiency is pathogenic for AD. Cellular, molecular, and functional changes were examined in adult/aging GluN3A knockout (KO) mice. The GluN3A KO mouse brain displayed age‐dependent moderate but persistent neuronal hyperactivity, elevated intracellular Ca 2+ , neuroinflammation, impaired synaptic integrity/plasticity, and neuronal loss. GluN3A KO mice developed olfactory dysfunction followed by psychological/cognitive deficits prior to amyloid‐β/tau pathology. Memantine at preclinical stage prevented/attenuated AD syndromes. AD patients’ brains show reduced GluN3A expression. We propose that chronic “degenerative excitotoxicity” leads to sporadic AD, while GluN3A represents a primary pathogenic factor, an early biomarker, and an amyloid‐independent therapeutic target.