Role of Glutamate and NMDA Receptors in Alzheimer’s Disease

Wang, Rui; Reddy, P. Hemachandra

doi:10.3233/jad-160763

Cited by 773 publications

(570 citation statements)

References 72 publications

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“…Histological examination of postmortem brains from AD patients revealed two major pathological hallmarks—intracellular neurofibrillary tangles and extracellular neuritic plaques. AD is also associated with synaptic damage, mitochondrial abnormalities, inflammatory responses, hormonal changes, and cell cycle abnormalities [1, 6–10]. Currently, 5.4 million Americans suffer with AD, including 5.2 million people age 65 and older and 200,000 individuals under the age of 65.…”

Section: Introductionmentioning

confidence: 99%

Therapeutics of Neurotransmitters in Alzheimer’s Disease

Kandimalla

Reddy

2017

JAD

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202

143

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterized by the loss of memory, multiple cognitive impairments and changes in the personality and behavior. Several decades of intense research have revealed that multiple cellular changes are involved in disease process, including synaptic damage, mitochondrial abnormalities and inflammatory responses, in addition to formation and accumulation of amyloid-β (Aβ) and phosphorylated tau. Although tremendous progress has been made in understanding the impact of neurotransmitters in the progression and pathogenesis of AD, we still do not have a drug molecule associated with neurotransmitter(s) that can delay disease process in elderly individuals and/or restore cognitive functions in AD patients. The purpose of our article is to assess the latest developments in neurotransmitters research using cell and mouse models of AD. We also updated the current status of clinical trials using neurotransmitters’ agonists/antagonists in AD.

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Section: Introductionmentioning

confidence: 99%

Therapeutics of Neurotransmitters in Alzheimer’s Disease

Kandimalla

Reddy

2017

JAD

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202

143

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“…More specifically, synaptic dysfunction in Alzheimer disease is thought to be secondary to altered NMDA receptor function, leading to aberrant handling of intracellular Ca 2+ , excitotoxicity, loss of synapses, and ultimately, neuronal death (reviewed by Mota et al (2014)). Moreover, modulation of NMDA receptor function with the low-affinity NMDA blocker memantine is one of the main therapeutic options for moderate to severe Alzheimer disease (reviewed by Danysz and Parsons (2003); Wang and Reddy (2017)). Although the specific relationship between Panx1 and GluN2D remains to be explored, work by others have implicated Panx1 in synaptic dysfunction during anoxia/ischemia and excitotoxicity through a mechanism involving a noncanonical metabotropic NMDA signalling pathway coupling Src kinases to Panx1 pore opening (Weilinger et al, 2016;Weilinger et al, 2012).…”

Section: Panx1 Interacting Proteins In Neurodegenerative Diseases: Amentioning

confidence: 99%

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

Frederiksen

Wicki-Stordeur

Swayne

2019

Preprint

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The Pannexin 1 (Panx1) channel-forming protein is enriched in the central nervous system, and has been associated with several critical neurodevelopmental and plasticity functions; these include dendritic spine formation, neuronal network development, synaptic plasticity, and pathological brain states such as ischemia, epilepsy, and neurodegeneration. Despite major advances in understanding the properties and activation modes of Panx1, the Panx1 interactome remains largely uncharacterized. Considering that Panx1 has been implicated in critical neurodevelopmental and neurodegenerative processes and diseases, we investigated the Panx1 interactome (482 Panx1interacting proteins) identified from mouse N2a cells. These proteins were cross-analyzed with the postsynaptic proteome of the adult mouse brain previously identified by mass spectrometry (LC-MS/MS), and neurodegenerative disease and neurodevelopmental disorder susceptibility genes previously identified by genome-wide association studies (GWAS); and then further investigated using various bioinformatics tools (PAN-THER, GO, KEGG and STRING databases). A total of 104 of the Panx1-interacting proteins were located at the postsynapse, and 99 of these formed a 16-cluster protein-protein interaction (PPI) network (hub proteins: Eef2, Rab6A, Ddx39b, Mapk1, Fh1, Ndufv1 et cetera). The cross-analysis led to the discovery of proteins and candidate genes involved in synaptic function and homeostasis. Of particular note, our analyses also revealed that certain Panx1-interacting proteins are implicated in Parkinson disease, Alzheimer disease, Huntington disease, amyotrophic lateral sclerosis, schizophrenia, autism spectrum disorder and epilepsy. Altogether, our work revealed important clues to the role of Panx1 in neuronal function in health and disease by expanding our knowledge of the PPI network of Panx1, and unveiling previously unidentified Panx1-interacting proteins and networks involved in biological processes and disease. Panx1 | PPIs | pathway analysis | neurodegenerative diseases | neurodevelopmental disorders | Parkinson disease | Alzheimer disease | chaperones | vesicle-mediated transportFunctional annotation, categorization and overrepresentation analyses of the Panx1 interactome using the PANTHER database. Bioinformatics analysis of all proteins in our Panx1-interacting protein list (using UniProt accession numbers) was carried out using the PANTHER database v14.1 (Mi et al., 2013;Thomas et al., 2003), which is a curated database that includes several bioinformatics tools. The proteins (or their corresponding genes, depending on the nature of the analysis) were annotated to (i) PAN-THER protein classes from the PANTHER protein class ontology, (ii) gene ontology (GO) terms within the biological process, molecular function and cellular component domains from the GO knowledge base and (iii) PANTHER pathways created using the CellDesigner tool, a modelling tool for biochemical networks (Funahashi et al., 2008;Mi et al., 2019a;Mi et al., 2013). Note that PANTHER pa...

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“…Rui Wang and P. Hemachandra Reddy discuss the role of glutamate and NMDA receptors (NMDAR) in AD [19]. Excitatory glutamatergic neurotransmission via NMDAR is critical for synaptic plasticity and survival of neurons.…”

Section: Current Status Of Neurotransmitters and Alzheimer’s Diseasementioning

confidence: 99%

“…Studies indicate that NMDAR-mediated responses are induced by regionalized receptor activities, followed by different downstream signaling pathways. They report that excessive, extra-synaptic NMDAR activity can be selectively blocked by the drug memantine, an NMDAR antagonist [19]. …”

Section: Current Status Of Neurotransmitters and Alzheimer’s Diseasementioning

confidence: 99%

A Critical Assessment of Research on Neurotransmitters in Alzheimer’s Disease

Reddy

2017

JAD

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The purpose of this mini-forum, “Neurotransmitters and Alzheimer’s Disease”, is to critically assess the current status of neurotransmitters in Alzheimer’s disease. Neurotransmitters are essential neurochemicals that maintain synaptic and cognitive functions in mammals, including humans, by sending signals across pre- to post-synaptic neurons. Authorities in the fields of synapses and neurotransmitters of Alzheimer’s disease summarize the current status of basic biology of synapses and neurotransmitters, and also update the current status of clinical trials of neurotransmitters in Alzheimer’s disease. This article discusses the prevalence, economic impact, and stages of Alzheimer’s dementia in humans.

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Role of Glutamate and NMDA Receptors in Alzheimer’s Disease

Cited by 773 publications

References 72 publications

Therapeutics of Neurotransmitters in Alzheimer’s Disease

Therapeutics of Neurotransmitters in Alzheimer’s Disease

Overlap in synaptic neurological condition susceptibility pathways and the neural pannexin 1 interactome revealed by bioinformatics analyses

A Critical Assessment of Research on Neurotransmitters in Alzheimer’s Disease

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