APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms
APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms
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DOI：
10.1038/mp.2013.194
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发表时间：
2014-11-01
影响因子：
11
通讯作者：
Goldberg, T. E.
中科院分区：
文献类型：
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作者：
Conejero-Goldberg, C.;Gomar, J. J.;Goldberg, T. E.
常见的 APOE2 基因变体具有神经保护作用，可预防阿尔茨海默病 (AD)，并将风险降低近 50%。然而，APOE2 赋予神经保护的机制在很大程度上尚不清楚。在这里，我们发现人类死后皮质中的 ApoE 蛋白丰度遵循异构体依赖性模式 (E2>E3>E4)。我们还通过微阵列确定了独特的下游转录谱，其特征是在 E2 病例中长时程增强 (LTP) 相关转录本的下调和细胞外基质 (ECM)/整合素相关转录本的上调，并通过证明 ECM 胶原蛋白和层粘连蛋白的增加在蛋白质水平证实了这一发现。对健康老年人的体内研究表明，E2 携带者具有独特且有利的生物标志物特征。 APOE2 还将轻度认知障碍转变为 AD 的风险降低了一半。我们的研究结果表明，ApoE2 蛋白丰度及其无法与 LDLR 结合，可能会增加β-淀粉样蛋白 (Ab) 的清除率。此外，ECM 增加和 LTP 相关表达减少会导致活性依赖性抗体分泌和/或兴奋毒性减少，从而也促进神经保护。
The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.