Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer's disease pathology

Mishizen-Eberz, Amanda J.; Rissman, Robert A.; Carter, Troy L.; Ikonomović, Miloš D.; Wolfe, Barry B.; Armstrong, David M.

doi:10.1016/j.nbd.2003.09.016

Cited by 141 publications

(89 citation statements)

References 47 publications

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“…Reports have indicated that the function of NMDARs decreases in AD, including gene expression (Yashiro and Philpot, 2008), levels of mRNA and protein (Hynd et al, 2001), or neurotransmitters (Rupsingh et al, 2011). A decline in levels of NMDAR subunits has been observed in many AD models and clinical research (Hynd et al, 2004;Mishizen-Eberz et al, 2004;Kravitz et al, 2013), which is consistent with our result that NMDAR1 and NMDAR2B expression decreased in SAMP8 as compared with SAMR1 mice. The decreased level of NMDAR limited its normal functional role, leading to a deficit in learning and memory.…”

Section: Hps Treatment Reverses the Changes In Level Of Nmda Subunitssupporting

confidence: 91%

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice

Wang

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Objectives: The aim of the study is to evaluate the cognitive-enhancing effects of hydrolysate of polygalasaponin (HPS) on senescence accelerate mouse P8 (SAMP8) mice, an effective Alzheimer's disease (AD) model, and to research the relevant mechanisms. Methods: The cognitive-enhancing effects of HPS on SAMP8 mice were assessed using Morris water maze (MWM) and step-through passive avoidance tests. Then N-methyl-D-aspartate (NMDA) receptor subunit expression for both the cortex and hippocampus of mice was observed using Western blotting. Results: HPS (25 and 50 mg/kg) improved the escape rate and decreased the escape latency and time spent in the target quadrant for the SAMP8 mice in the MWM after oral administration of HPS for 10 d. Moreover, it decreased error times in the passive avoidance tests. Western blotting showed that HPS was able to reverse the levels of NMDAR1 and NMDAR2B expression in the cortex or hippocampus of model mice. Conclusions: The present study suggested that HPS can improve cognitive deficits in SAMP8 mice, and this mechanism might be associated with NMDA receptor (NMDAR)-related pathways.

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Section: Hps Treatment Reverses the Changes In Level Of Nmda Subunitssupporting

confidence: 91%

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice

Wang

et al. 2016

J. Zhejiang Univ. Sci. B

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“…4,5) It has been reported that NR1 and NR2B mRNA levels decrease in patients with AD associated with progression of the neuropathology. 10) We reported previously that CRE-dependent transcription was enhanced by nobiletin by activation of the PKA/MEK/ERK/ CREB signal pathway in PC12D cells. 15,20) Moreover, our previous report showed that nobiletin ameliorates the NMDA receptor antagonist-induced learning impairment in association with ERK activation in mice.…”

Section: Discussionmentioning

confidence: 91%

“…9) Furthermore, NR1 and NR2B subunit mRNA and protein levels decrease significantly in patients with AD, and the degree of decrease is associated with progression of the neuropathology. 10) Recent studies have demonstrated that learning and memory requires expression of large number of genes that are associated with the cAMP response element (CRE)-binding protein (CREB). [11][12][13] Elevated Ca 2+ level then triggers multiple protein kinase signal pathways that activate LTP by activating protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK/CREB.…”

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confidence: 99%

Upregulation of <i>N</i>-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

Kimura

Nemoto

Degawa

et al. 2014

Biological & Pharmaceutical Bulletin

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The N-methyl-D-aspartate (NMDA) receptor plays a key role in learning and memory. Our recent studies have shown that nobiletin from citrus peels activates the cAMP response element-binding protein (CREB) signaling pathway and ameliorates NMDA receptor antagonist-induced learning impairment by activating extracellular signal-regulated kinase. For the first time, we have shown that nobiletin significantly upregulated mRNA expression of the NMDA receptor subunits NR1, NR2A, and NR2B in PC12D cells. Furthermore, c-Fos mRNA expression also increased due to the action of nobiletin. Our results indicate that nobiletin modulates the expression of essential genes for learning and memory by activating the CREB signaling pathway, and suggest that this action mechanism of nobiletin plays a crucial role in improving NMDA receptor antagonist-induced learning impairment in model animals with dementia.Key words nobiletin; N-methyl-D-aspartate receptor; c-Fos; gene expression; memory impairment; dementia Alzheimer's disease (AD) is an age-related neurodegenerative disorder with progressive learning and memory impairment. The rise in the number of patients with AD is a severe social problem worldwide. It is now widely recognized that the synaptic dysfunction and neurodegeneration in AD is caused by amyloid β (Aβ). 1,2)It is well-known that the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor, plays a very important role in learning and memory functions and is widely distributed in the brain, notably in the CA1 region of the hippocampus. 3)This receptor is constructed from NR1 and distinct NR2 (A, B, C, or D) subunits. In particular, binding of glutamate requires both NR1 and NR2 subunits; functional NR1/NR2A and NR1/NR2B receptors have a particularly close relationship with long-term potentiation (LTP) that is a form of synaptic plasticity. 4) Cognitive impairment is caused by hypofunction of the NMDA receptor.5) The NR1 subunit is prerequisite for acquisition of spatial memory, object recognition, olfactory discrimination, and contextual fear memory in the hippocampal CA1, 6,7) whereas the NR2A subunit is required for LTP at the hippocampal CA1 synapses, 8) and NR2B contributes to the maintenance of spatial performance. 9) Furthermore, NR1 and NR2B subunit mRNA and protein levels decrease significantly in patients with AD, and the degree of decrease is associated with progression of the neuropathology. 10)Recent studies have demonstrated that learning and memory requires expression of large number of genes that are associated with the cAMP response element (CRE)-binding protein (CREB).11-13) Elevated Ca 2+ level then triggers multiple protein kinase signal pathways that activate LTP by activating protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK/CREB. As a consequence of CREB activation, transcriptional regulators such as c-Fos, c-jun, and fra1 are activated that cause secondary expression of numerous molecules related to learning and memory.11) In particular, c-Fos constructs activator p...

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“…The overlap of these changes with those of Alzheimer´s pathology suggests that low dose rate irradiation may be involved in the development of Alzheimer´s disease [7]. In the United States, analysis of AD death rates versus radon background radiation and total background angiogenesis [18], up-regulation of NMDA receptor subunit 1 (NR1) and NR2A [19], changes of synaptic proteins such as MAP-2 and PSD-95 [20], accumulation of ubiquitin inclusion bodies, autophagosome [21] and down-regulation of neurotrophic factors such as brainderived neurotrophic factor (BDNF) [22] may induce neuritic plaques, neurofibritlary tangles and neuropil threads leading to the development of Alzheimer's disease (Figure 1). …”

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confidence: 99%

Radiation and Alzheimer's Disease (AD)

Tang¹

2018

J Alzheimers Dis Parkinsonism

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radiation suggested that ionizing radiation was a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiated AD [8]. The Alzheimer neurofibrillary tangle is composed of tau, which is one of the most common pathological hallmarks of AD and tau aggregation pathology at Braak stage 1 1 (out of 6 Braak stages) or beyond affects 50% of the population over the age of 45 [9][10][11]. Our recent review of the effect of the pre-and post-natal irradiation on animal models and human studies indicated many similarities in hippocampal neuropathology, cognitive impairment and relevant molecular mechanisms between Alzheimer's disease and early life radiation exposure-induced neuropsychological disorders [12][13][14][15][16]. It suggests that irradiation of the brain in early human life may set abnormal developmental events into motion that starts from tau aggregation at the ages of 40s and 50s, leading to the development of Alzheimer's Disease at the late stages of human life. Alzheimer's disease (AD) is the most common form of dementia, and accounts for 60 to 80 percent of dementia cases. While about onethird of all people age 85 and older may have Alzheimer's disease, and the number of people with the disease doubles every 5 years beyond age 65, its early onset may start from the ages of 40s and 50s. Old age and genetic factor are two most important factors for the development of Alzheimer's disease. Epidemiological studies have suggested that excessive alcohol consumption, smoking, environmental toxin such as pesticides (Dichlorodiphenyltrichloroethane or DDT), food additives (such as nitrogen-based chemicals which are converted to toxic nitrosamines during cooking), contamination ( mussels contaminated with demonic acid), food components (two amino acids in seeds of certain legumes which enhance the action of the neurotransmitter glutamate), air pollution (such as aerosolized nickel nanoparticles, a component of air pollution) may also play important roles in the development of the disease [1]. Serious head injury, heart disease, diabetes, stroke, high blood pressure and high cholesterol which damage the heart and blood vessels may be indirectly related to the development of AD due to the increase of β-amyloid (Aβ).Recent systematic review of bibliographic databases from PubMed, EMBASE, Cochrane Library and Web of Science suggests that occupational exposure to extremely low frequency magnetic fields (ELF-MF) to welders, electric utility workers, train drivers and sewing machine operators may increase the risk of AD [2,3]. Experimental studies indicated that low-dose radiation exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. Nine neural signaling pathways had a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated) and in brain tissue from patients...

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Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer's disease pathology

Cited by 141 publications

References 47 publications

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice

Upregulation of <i>N</i>-Methyl-D-aspartate Receptor Subunits and c-Fos Expressing Genes in PC12D Cells by Nobiletin

Radiation and Alzheimer's Disease (AD)

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