Genetic Variation in N-Methyl-D-Aspartate Receptor Subunit NR3A but Not NR3B Influences Susceptibility to Alzheimer’s Disease

Liu, Hsin Ping; Lin, Wei-Yong; Liu, Shu Hsiang; Wang, Wen Fu; Tsai, Chon Haw; Wu, Bor Tsang; Wang, Chien-Kuo; Tsai, Fuu Jen

doi:10.1159/000254757

Cited by 24 publications

(17 citation statements)

References 93 publications

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“…In addition to changes in the NMDA receptors, the genetic variation encoding the receptors could also affect cognitive dysfunction in AD. Data from a case-control study conducted by Liu et al confirms that the exonic polymorphisms of NR3A, but not NR3B, are an important risk factor for AD pathogenesis among the Taiwanese population (Liu et al, 2009). One stereotaxic and genome-wide study confirmed that one SNP, rs10845840, which encodes the NMDA receptor NR2B subunit, is associated with temporal lobe volume and has proven to be a more informative phenotype than hippocampal volumes in AD (Stein et al, 2010).…”

Section: Alterations In Neurotransmitter Receptors In Alzheimer’s mentioning

confidence: 93%

Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Yan

Zhou

et al. 2012

Progress in Neurobiology

250

139

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Cognitive dysfunction is one of the most typical characteristics in various neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease (advanced stage). Although several mechanisms like neuronal apoptosis and inflammatory responses have been recognized to be involved in the pathogenesis of cognitive dysfunction in these diseases, recent studies on neurodegeneration and cognitive dysfunction have demonstrated a significant impact of receptor modulation on cognitive changes. The pathological alterations in various receptors appear to contribute to cognitive impairment and/or deterioration with correlation to diversified mechanisms. This article recapitulates the present understandings and concepts underlying the modulation of different receptors in human beings and various experimental models of Alzheimer’s disease and Parkinson’s disease as well as a conceptual update on the underlying mechanisms. Specific roles of serotonin, adrenaline, acetylcholine, dopamine receptors, and N-methyl-D-aspartate receptors in Alzheimer’s disease and Parkinson’s disease will be interactively discussed. Complex mechanisms involved in their signaling pathways in the cognitive dysfunction associated with the neurodegenerative diseases will also be addressed. Substantial evidence has suggested that those receptors are crucial neuroregulators contributing to cognitive pathology and complicated correlations exist between those receptors and the expression of cognitive capacities. The pathological alterations in the receptors would, therefore, contribute to cognitive impairments and/or deterioration in Alzheimer’s disease and Parkinson’s disease. Future research may shed light on new clues for the treatment of cognitive dysfunction in neurodegenerative diseases by targeting specific alterations in these receptors and their signal transduction pathways in the frontal-striatal, fronto–striato–thalamic, and mesolimbic circuitries.

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Section: Alterations In Neurotransmitter Receptors In Alzheimer’s mentioning

confidence: 93%

Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Yan

Zhou

et al. 2012

Progress in Neurobiology

250

139

View full text Add to dashboard Cite

show abstract

“…Liu et al [80] studied the potential association of polymorphisms in NMDA receptor subunits NR3A and NR3B, encoded by the GRIN3A and GRIN3B genes, with AD, on the basis that memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may provide some clinical benefit in AD patients. Two SNPs, 3104G/A (rs10989563) and 3723G/A (rs3739722), in the GRIN3A gene, and two GRIN3B gene polymorphisms, 1210C/T (rs4807399) and 1730C/T (rs2240158), were analyzed.…”

Section: Structural Genomics Of Alzheimer's Diseasementioning

confidence: 99%

Genomics of Dementia:APOE- andCYP2D6-Related Pharmacogenetics

Cacabelos

Martínez

Fernández‐Novoa

et al. 2012

International Journal of Alzheimer's Disease

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Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.

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“…Liu et al [75] studied the potential association of polymorphisms in NMDA receptor subunits NR3A and NR3B, encoded by the GRIN3A and GRIN3B genes, with AD, on the basis that memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may provide some clinical benefit in AD patients. Two SNPs, 3104G/A (rs10989563) and 3723G/A (rs3739722), in the GRIN3A gene, and two GRIN3B gene polymorphisms, 1210C/T (rs4807399) and 1730C/T (rs2240158), were analyzed.…”

Section: Genomics Of Dementiamentioning

confidence: 99%

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

et al. 2010

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About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.

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Genetic Variation in N-Methyl-D-Aspartate Receptor Subunit NR3A but Not NR3B Influences Susceptibility to Alzheimer’s Disease

Cited by 24 publications

References 93 publications

Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Neurotransmitter receptors and cognitive dysfunction in Alzheimer's disease and Parkinson's disease

Genomics of Dementia:APOE- andCYP2D6-Related Pharmacogenetics

Future Trends in the Pharmacogenomics of Brain Disorders and Dementia: Influence of APOE and CYP2D6 Variants

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