Karthick Chennakesavan, Nithiyanandan Saravanan, Essa Musthafa Mohamed, Guillemin Gilles J, Jayachandran Swaminathan K, Anusuyadevi Muthuswamy
a Molecular Gerontology Laboratory, Department of Biochemistry , School of Life Sciences, Bharathidasan University , Tiruchirappalli , India.
b Department of Food Science and Nutrition , College of Agriculture and Marine Sciences, Sultan Qaboos University , Muscat , Oman.
Neurol Res. 2019 Feb;41(2):139-150. doi: 10.1080/01616412.2018.1544745. Epub 2018 Nov 19.
Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aβ) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aβ influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aβ (oAβ) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD.
Aggregated forms of synthetic Aβ peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription-polymerase chain reaction.
oAβ decreased the gene expression level of α7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAβ aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, amyloid-β are highly expressed in 15 days after postinjection in hippocampus of adult rats.
Acute exposure of oAβ modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments.
AD: Alzheimer's disease, Aβ: amyloid-β; oAβ: oligomeric amyloid-β 1-42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d-aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; α7-nAChR: α7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T.
阿尔茨海默病（AD）的特征是不溶性β淀粉样蛋白（Aβ）肽斑异常沉积、缠结形成和突触功能障碍。这些导致神经回路功能受损，并由于神经递质受体的激活而改变行为反应。最近，有研究表明Aβ会影响AD中N-甲基-D-天冬氨酸（NMDA）受体的激活；然而，其潜在的分子机制仍不清楚。因此，本研究旨在探讨在AD大鼠模型中，寡聚Aβ（oAβ）对编码NMDA和乙酰胆碱受体基因的mRNA表达的时间进程影响。
采用立体定向手术将合成的Aβ肽聚集形式双侧注射到大鼠脑海马区内。在实验期末，使用八臂放射状迷宫任务进行行为分析。处死大鼠后，取脑海马组织，采用半定量逆转录-聚合酶链反应研究谷氨酸能和胆碱能受体的mRNA表达。
oAβ降低了α7-烟碱型乙酰胆碱受体的基因表达水平，增加了NMDA受体2A和2B亚基的mRNA表达。特别是，oAβ聚集物在注射15天后增加了大鼠的停留时间并改变了行为反应。此外，注射后15天，淀粉样β蛋白在成年大鼠海马中高表达。
oAβ的急性暴露调节了成年大鼠海马中谷氨酸能和胆碱能受体的差异基因表达，且具有时间依赖性，反映了学习和记忆障碍背后海马回路系统的变化。
AD：阿尔茨海默病；Aβ：β淀粉样蛋白；oAβ：寡聚淀粉样β1-42全长肽；CAM：钙调蛋白；CNS：中枢神经系统；CR：刚果红；DG：齿状回；EC：内嗅皮质；HFIP：1,1,1,3,3,3-六氟-2-丙醇；IBO：鹅膏蕈氨酸；NMDA：N-甲基-D-天冬氨酸；NMDAR：N-甲基-D-天冬氨酸受体；NR2A：N-甲基-D-天冬氨酸受体2A；NR2B：N-甲基-D-天冬氨酸受体2B；ACh：乙酰胆碱；α7-nAChR：α7-烟碱型乙酰胆碱受体；PBS：磷酸盐缓冲盐水；RAM：放射状迷宫；ThT：硫黄素T
