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

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.

The Role of TRPA1 Channels in the Central Processing of Odours Contributing to the Behavioural Responses of Mice

“…A possible mechanism of neurodegeneration may be the activation of TRPA1 channels leading to an increased calcium influx, triggering neuronal activation on one hand and in the case of excessive function, neuronal apoptosis. This process may occur in the glutamatergic excitatory neurons of the OB and PC and-together with consecutive glutamatergic excitotoxicity-may explain the appearance of anosmia in neurodegenerative diseases (e.g., Parkinson's, Alzheimer's) [62][63][64] 5-10 years prior to the emergence of other neurological symptoms [30,31].…”

Application of Marine Natural Products against Alzheimer’s Disease: Past, Present and Future

“…Ca 2+ dysregulation is a common and pervasive pathophysiological phenomenon in AD. Zhong et al [ 27 ] hypothesized that N-methyl-D-aspartate receptor subunit (GluN3A) is essential for sustained Ca 2+ homeostasis and its deficiency is a causative factor in AD. By examining cellular, molecular and functional changes in adult/senescent GluN3A knockout (KO) mice, they concluded that chronic ‘degenerative excitotoxicity’ can lead to sporadic AD, and GluN3A is the main pathogenic factor, a lifelong moderate but sustained Ca 2+ overload is a causal pathogenic mechanism of sporadic AD.…”

“…By examining cellular, molecular and functional changes in adult/senescent GluN3A knockout (KO) mice, they concluded that chronic ‘degenerative excitotoxicity’ can lead to sporadic AD, and GluN3A is the main pathogenic factor, a lifelong moderate but sustained Ca 2+ overload is a causal pathogenic mechanism of sporadic AD. Therefore, GluN3A may be an amyloid-independent therapeutic target [ 27 ].…”

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology

“…Accumulation of Aβ oligomers has been observed in the synapses of glutamatergic neurons in AD brains [196,197]. Although plenty of studies have demonstrated that Aβ mediates neurotoxicity by directly or indirectly regulating NMDARs [6,[198][199][200][201][202], and NMDAR antagonists can rescue Aβ-induced damage [116,203], interestingly, genetic deletion of the NMDAR subunit GluN3A results in neuropathological changes like AD, including psychological/cognitive deficits and amyloid-β/tau pathology [204]. Moreover, blocking NMDARs may reduce neurodegeneration [205].…”