Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A.
Pathogenesis of sporadic Alzheimer's disease by deficiency of NMDA receptor subunit GluN3A.
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DOI：
10.1002/alz.12398
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Yu SP
中科院分区：
文献类型：
--
作者：
Zhong W;Wu A;Berglund K;Gu X;Jiang MQ;Talati J;Zhao J;Wei L;Yu SP
阿尔茨海默病（AD）的Ca 2+假说认为Ca 2+稳态失调是AD的常见机制;然而，Ca 2+失调的原因尚不清楚。同时，NMDA受体（NMDARs），钙内流的主要介质，高活性的AD报道。GluN 3A（NR 3A）是NMDAR抑制亚基。我们推测GluN 3A对Ca ~（2+）稳态是至关重要的，它的缺乏是AD的致病因素。研究了GluN 3A基因敲除（KO）小鼠衰老过程中细胞、分子和功能的变化。GluN 3A KO小鼠脑显示年龄依赖性中度但持续的神经元过度活跃、细胞内Ca 2+升高、神经炎症、突触完整性/可塑性受损和神经元丢失。GluN 3A KO小鼠在Aβ/tau病理学之前出现嗅觉功能障碍，随后出现心理/认知缺陷。美金刚在临床前阶段预防/减弱AD综合征。AD患者的大脑显示GluN 3A表达减少。我们认为慢性“退行性兴奋毒性”导致散发性AD，而GluN 3A代表主要致病因子、早期生物标志物和淀粉样蛋白非依赖性治疗靶点。
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 NMDA receptors (NMDARs), the primary mediator of Ca2+ influx, are reported in AD. GluN3A (NR3A) is a NMDAR inhibitory subunit. We hypothesize that GluN3A is critical for Ca2+ homeostasis, its deficiency is pathogenic for AD. Cellular, molecular and functional changes were examined in GluN3A knockout (KO) mice during aging. 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 Aβ/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.
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DOI：
10.1002/neu.480230915
发表时间：
1992-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
CHOI, DW
通讯作者：
CHOI, DW
影响因子：
14
作者：
Angulo, Sergio L.;Henzi, Thomas;Moreno, Herman
通讯作者：
Moreno, Herman
影响因子：
14
作者：
通讯作者：
--
影响因子：
3.6
作者：
Devi, Latha;Ohno, Masuo
通讯作者：
Ohno, Masuo
DOI：
10.1073/pnas.90.2.567
发表时间：
1993-01-15
影响因子：
11.1
作者：
ARISPE, N;ROJAS, E;POLLARD, HB
通讯作者：
POLLARD, HB