Dataset Information

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.

SUBMITTER: Zhong W

PROVIDER: S-EPMC8685302 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Zhong Weiwei W Wu Anika A Berglund Ken K Gu Xiaohuan X Jiang Michael Qize MQ Talati Jay J Zhao Jingjie J Wei Ling L Yu Shan Ping SP

Alzheimer's & dementia : the journal of the Alzheimer's Association 20210620 2

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 ...[more]

PMID: 34151525

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Project description:The glutamate-gated ion channels known as N-methyl-d-aspartate receptors (NMDARs) are important for both normal and pathological brain function. Subunit-selective antagonists have high therapeutic promise since many pathological conditions involve NMDAR over activation, although few clinical successes have been reported. Allosteric inhibitors of GluN2B-containing receptors are among the most potential NMDAR targeting drugs. Since the discovery of ifenprodil, a variety of GluN2B-selective compounds have been discovered, each with remarkably unique structural motifs. These results expand the allosteric and pharmacolog-ical spectrum of NMDARs and provide a new structural basis for the development of next-generation GluN2B antagonists that have therapeutic potential in brain diseases. Small molecule therapeutic inhibitors targeting NMDA have recently been developed to target CNS disorders such as Alzheimer's disease. In the current study, a cheminformatics method was used to discover potential antagonists and to identify the structural requirements for Gly/NMDA antagonism. In this case we have created a useful pharmacophore model with solid statistical values. Through pharmacophore mapping, the verified model was used to filter out virtual matches from the ZINC database. Assessing receptor-ligand binding mechanisms and affinities used molecular docking. To find the best hits, the GlideScore and the interaction of molecules with important amino acids were considered essential features. We found some molecular inhibitors, namely, ZINC13729211, ZINC07430424, ZINC08614951, ZINC60927204, ZINC12447511, and ZINC18889258 with high binding affinity using computational methods. The molecules in our studies showed characteristics such as good stability, hydrogen bonding and higher binding affinities in the solvation-based assessment method than ifenprodil with acceptable ADMET profile. Moreover, these six leads have been proposed as potential new perspectives for exploring potent Gly/NMDA receptor antagonists. In addition, it can be tested in the laboratory for potential therapeutic strategies for both in vitro and in vivo research.

Dataset Information

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

Publications

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

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