Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex.
Apolipoprotein E level and cholesterol are associated with reduced synaptic amyloid beta in Alzheimer's disease and apoE TR mouse cortex.
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DOI：
10.1007/s00401-011-0892-1
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发表时间：
2012-01
影响因子：
12.7
通讯作者：
Gylys KH
中科院分区：
文献类型：
--
作者：
Arold S;Sullivan P;Bilousova T;Teng E;Miller CA;Poon WW;Vinters HV;Cornwell LB;Saing T;Cole GM;Gylys KH
载脂蛋白 E4 等位基因 (APOE4) 会增加阿尔茨海默病 (AD) 的风险，而 APOE2 具有保护作用，但相关的细胞机制尚不清楚。我们使用流式细胞术分析来测量 AD 和老年认知正常对照的大量突触末端中载脂蛋白 E (apoE) 和淀粉样蛋白 β 肽 (Aβ) 水平，并证明在 AD 皮质突触和 AD APP/PS1 大鼠模型中，随着 Aβ 升高，可溶性 apoE 水平适度但显着增加。双标记实验记录了 apoE 和 Aβ 在单个突触中的共定位，以及 AD 和对照中一小群 apoE 阳性突触中 Aβ 的浓度。与清除作用一致，对照病例中 Aβ 阳性突触的 apoE 水平较高。在表达人 apoE 的老年靶向替代小鼠中，与 apoE3/3 和 apoE4/4 系相比，apoE2/4 突触末端表现出最高水平的 apoE 和最低水平的 Aβ。在apoE2/4末端，apoE和Aβ的免疫标记模式与人类对照病例中的模式非常相似，并且apoE升高伴随着apoE2/4突触末端游离胆固醇的升高。这些结果与 APOE 在 AD 突触中 Aβ 清除中的作用一致，并表明与 E3 和 E4 相比，apoE2 的最佳脂化对 Aβ 清除和突触功能做出了重要贡献。
The apolipoprotein E4 allele (APOE4) contributes to Alzheimer’s disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aβ) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aβ in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aβ in individual synapses with concentration of Aβ in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aβ-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aβ compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aβ closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aβ clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aβ clearance and synaptic function.
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影响因子：
2.7
作者：
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通讯作者：
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