E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease
E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease
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DOI：
10.1212/wnl.54.2.403
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发表时间：
2000-01-25
期刊：
影响因子：
9.9
通讯作者：
Thal, LJ
中科院分区：
文献类型：
--
作者：
Corey-Bloom, J;Tiraboschi, P;Thal, LJ
目的：探讨载脂蛋白E(APOE)基因与阿尔茨海默病(AD)胆碱能功能障碍和突触丢失的关系。背景：阿尔茨海默病患者新皮质突触减少，胆碱能系统明显丧失。已有研究表明，APOE epsilon 4等位基因数目与胆碱乙酰转移酶(ChAT)活性呈负相关，从而影响胆碱能功能。目前尚不清楚载脂蛋白E基因是否会影响新皮质突触丢失。方法：对182例AD患者(美国国家老龄研究所和建立阿尔茨海默病标准登记处联盟)和16名正常对照(NC)进行尸检。在血液样本或死后脑组织中检测APOE基因。突触素(Synaptophysin，Syn)的斑点免疫结合法测定额叶中叶突触计数(AU/mUg)。额叶中段ChAT活性(nmoL/h/100 mg)用标准方法测定。结果：AD患者额叶中段ChAT活性和Syn均显著低于正常对照组。AD患者ChAT活性与epsilon 4等位基因拷贝数之间的关系较为复杂，有两个或无一个epsilon 4等位基因的AD患者ChAT活性低于有一个epsilon 4等位基因的患者。APOE基因与AD突触丢失无相关性。三种基因型的SYN密度几乎相同。结论：与其他研究不同的是，我们未能检测到AD患者中额叶皮质ChAT活性与epsilon 4等位基因拷贝数之间的线性关系。我们的数据还表明，epsilon 4等位基因的存在不会影响AD患者额叶中段突触的丢失。这表明，除APOE基因外的其他因素可能在AD患者额叶中段胆碱能功能和突触功能下降中起作用。
Objective: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD. Background: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon 4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear. Methods: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/mu g) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays. Results: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of epsilon 4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon 4 alleles compared with those with one epsilon 4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes. Conclusions: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of epsilon 4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of epsilon 4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.