| First Author | Zhong W | Year | 2022 |
| Journal | Alzheimers Dement | Volume | 18 |
| Issue | 2 | Pages | 222-239 |
| PubMed ID | 34151525 | Mgi Jnum | J:332866 |
| Mgi Id | MGI:7398354 | Doi | 10.1002/alz.12398 |
| Citation | Zhong W, et al. (2022) Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A. Alzheimers Dement 18(2):222-239 |
| abstractText | 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-beta/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. |
