Changes of several brain receptor complexes in the cerebral cortex of patients with Alzheimer disease: probable new potential pharmaceutical targets
Changes of several brain receptor complexes in the cerebral cortex of patients with Alzheimer disease: probable new potential pharmaceutical targets
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DOI：
10.1007/s00726-013-1623-9
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发表时间：
2014-01-01
期刊：
影响因子：
3.5
通讯作者：
Lubec, Gert
中科院分区：
文献类型：
--
作者：
Falsafi, Soheil Keihan;Rossner, Steffen;Lubec, Gert
虽然阿尔茨海默病（AD）与主要脑受体的缺陷有关，但迄今为止的研究仅限于受体亚单位的测定或特异性配体结合研究。然而，现有技术的可用性使得能够确定和定量脑受体复合物。因此，我们研究了AD患者大脑中天然受体复合物的水平。皮质组织从对照受试者（n = 12名女性和12名男性）和AD患者（n = 12名女性和12名男性）在3小时的尸检时间段内获得。将组织冷冻保存，直至进行进一步的生化分析。提取膜蛋白，随后使用蔗糖梯度通过超离心富集。然后将膜蛋白固定在天然凝胶上，并使用针对单个脑受体的抗体进行免疫印迹。我们发现，含有GluR 2、GluR 3和GluR 4以及5-HT 1的复合物的水平相当（A）。此外，在男性AD患者中，含有毒蕈碱AChR M1、NR 1和GluR 1的复合物的水平显著增加。在AD男性和女性中，尼古丁AChRs 4和7以及多巴胺能受体D1和D2也增加。这些发现揭示了受体复合物水平改变的模式，这可能导致这些受体的协同活性的恶化，从而导致在AD患者中观察到的认知缺陷。应该强调的是，受体复合物作为工作单位而不是单个亚基发挥作用。因此，所确定的受体缺陷可能与实验疗法的设计有关。因此，这些受体的特异性药理学调节在药物库内。
Although Alzheimer disease (AD) has been linked to defects in major brain receptors, studies thus far have been limited to the determination of receptor subunits or specific ligand binding studies. However, the availability of current technology enables the determination and quantification of brain receptor complexes. Thus, we examined levels of native receptor complexes in the brains of patients with AD. Cortical tissue was obtained from control subjects (n = 12 females and 12 males) and patients with AD (n = 12 females and 12 males) within a 3-h postmortem time period. The tissues were kept frozen until further biochemical analyses. Membrane proteins were extracted and subsequently enriched by ultracentrifugation using a sucrose gradient. Membrane proteins were then electrophoresed onto native gels and immunoblotted using antibodies against individual brain receptors. We found that the levels were comparable for complexes containing GluR2, GluR3 and GluR4 as well as 5-HT1(A). Moreover, the levels of complexes containing muscarinic AChR M1, NR1 and GluR1 were significantly increased in male patients with AD. Nicotinic AChRs 4 and 7 as well as dopaminergic receptors D1 and D2 were also increased in males and females with AD. These findings reveal a pattern of altered receptor complex levels that may contribute to the deterioration of the concerted activity of these receptors and thus result in cognitive deficits observed in patients with AD. It should be emphasised that receptor complexes function as working units rather than individual subunits. Thus, the receptor deficits identified may be relevant for the design of experimental therapies. Therefore, specific pharmacological modulation of these receptors is within the pharmaceutical repertoire.