Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A

Abstract

The Ca²⁺ hypothesis for Alzheimer's disease (AD) conceives Ca²⁺ dyshomeostasis as a common mechanism of AD; the cause of Ca²⁺ dysregulation, however, is obscure. Meanwhile, hyperactivities of N-Methyl-D-aspartate receptors (NMDARs), the primary mediator of Ca²⁺ influx, are reported in AD. GluN3A (NR3A) is an NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for sustained Ca²⁺ 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 Ca²⁺ , 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.

Keywords: Alzheimer's disease; N-methyl-d-aspartate receptor; NR3A; degenerative excitotoxicity; dementia; prevention; subhealth status.