Nordberg A
Department of NEUROTEC, Division of Molecular Neuropharmacology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden.
Biol Psychiatry. 2001 Feb 1;49(3):200-10. doi: 10.1016/s0006-3223(00)01125-2.
The neuronal nicotinic acetylcholine receptors (nAChRs) in the brain are important for functional processes, including cognitive and memory functions. The nAChRs acting as neuromodulators in communicative processes regulated by different neurotransmitters show a relatively high abundance in the human cortex, with a laminar distribution of the nAChRs of superhigh, high, and low affinity in the human cortex. The regional pattern of messenger RNA (mRNA) for various nAChR subtypes does not strictly follow the regional distribution of nAChR ligand-binding sites in the human brain. Consistent losses of nAChRs have been measured in vitro in autopsy brain tissue of Alzheimer's disease patients (AD), as well as in vivo by positron emission tomography (PET). Measurement of the protein content of nAChRs showed reduced levels of the alpha4, alpha3, and alpha7 nAChR subtypes. The finding that the alpha4 and alpha3 mRNA levels were not changed in AD brains suggests that the losses in high-affinity nicotinic-binding sites cannot be attributed to alterations at the transcriptional level of the alpha4 and alpha3 genes and that the causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of the alpha7 nAChR subtyep in the hippocampus indicates that subunit-specific changes in gene expression of the alpha7 nAChR might be associated with AD. The PET studies reveal deficits in nAChRs as an early phenomena in AD, stressing the importance of nAChRs as a potential target for drug intervention. PET ligands measuring the alpha4 nAChRs are under development. Studies of the influence of beta-amyloid on nAChRs in brain autopsy tissue from patients with the amyloid precursor protein 670/671 mutation have shown that there is no direct relationship between nAChR deficits and pathology. Treatment with cholinergic drugs in AD patients indicate improvement of the nAChRs in the brain, as visualized by PET. Further studies on neuroprotective mechanisms mediated via nAChR subtypes are exciting new avenues.
大脑中的神经元烟碱型乙酰胆碱受体（nAChRs）对包括认知和记忆功能在内的多种功能过程至关重要。作为由不同神经递质调节的交流过程中的神经调质，nAChRs在人类皮质中显示出相对较高的丰度，在人类皮质中具有超高、高和低亲和力nAChRs的层状分布。各种nAChR亚型的信使核糖核酸（mRNA）的区域模式并不严格遵循人脑nAChR配体结合位点的区域分布。在阿尔茨海默病患者（AD）的尸检脑组织中，以及通过正电子发射断层扫描（PET）在体内均已测量到nAChRs的持续减少。对nAChRs蛋白质含量的测量显示，α4、α3和α7 nAChR亚型的水平降低。α4和α3 mRNA水平在AD大脑中未发生变化这一发现表明，高亲和力烟碱结合位点的减少不能归因于α4和α3基因转录水平的改变，而必须在翻译和/或翻译后水平寻找原因。海马体中α7 nAChR亚型的mRNA水平升高表明，α7 nAChR基因表达的亚基特异性变化可能与AD有关。PET研究揭示了nAChRs缺陷是AD中的早期现象，强调了nAChRs作为药物干预潜在靶点的重要性。测量α4 nAChRs的PET配体正在研发中。对淀粉样前体蛋白670/671突变患者脑尸检组织中β-淀粉样蛋白对nAChRs影响的研究表明，nAChR缺陷与病理学之间没有直接关系。AD患者使用胆碱能药物治疗表明，PET显示大脑中的nAChRs有所改善。对通过nAChR亚型介导的神经保护机制的进一步研究是令人兴奋的新途径。
