Deficiency of NMDA receptor subunit GluN3A as a pathogenic factor for endogenous amyloid deposition and sporadic Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease, evolving amyloidosis and tau protein hyperphosphorylation, synapse dysfunction, neuron degeneration and cognitive deficits. Investigations based on the Aβ/tau hypothesis have been performed in transgenic animal models expression familial/mutated AD genes. However, treatments based on this hypothesis have not provided effective clinical therapies. Hyperactivity of the glutamatergic NMDA receptor (NMDAR) is a common pathophysiology of AD and has been viewed as a consequence of Aβ pathology. Among NMDAR subunits, GluN3A is a unique inhibitory subunit that suppresses NMDA currents and Ca2+ influx. Recent evidence from rodent and human studies shows that GluN3A is widely expressed and plays important functional roles in neonatal and adult brains. Ca2+ overload is a trigger of excitotoxicity, while GluN3A plays a regulatory role of Ca2+ homeostasis. The role of GluN3A regulation in AD is unknown.