APOE4 and Loss of Synaptic Integrity

描述(由申请人提供)：人类APOE4等位基因与早期发病和增加阿尔茨海默病(AD)的风险有关。早在阿尔茨海默病发作之前，APOE4携带者就可以发现认知缺陷。载脂蛋白E在中枢神经系统发育、神经元重塑和修复过程中起着维持突触完整性的作用。我们实验室使用人类载脂蛋白E靶向替换(TR)小鼠模型系统进行的研究为载脂蛋白E在突触完整性中的作用提供了支持证据。与apoES小鼠相比，年轻的(7个月)apoE4小鼠表现出明显的兴奋性突触活动和树突树枝，在任何与年龄相关的神经病理标记之前。与年龄匹配的apoE4小鼠的合作研究显示，与apoES小鼠相比，apoE4小鼠在记忆和海马LTP方面存在缺陷。我们计划确定突触缺陷何时开始，以及哪些大脑区域容易受到APOE4突触缺陷的影响。我们发现，与apoES小鼠相比，apoE4海马区的特定磷脂物种(即假定的必需脂肪酸(EFA))显著减少。这些类型的脂肪酸是有效突触功能所必需的。我们计划确定大脑其他区域的必需脂肪酸是否也有类似的减少。我们认为，观察到的apoE4突触缺陷可以部分解释为突触膜胆固醇和脂肪酸代谢的变化。因此，我们希望检验以下假设。我们认为，APOE4携带者在暴露于不健康的饮食中时，缺乏维持突触可塑性所需的足够水平的必需脂肪酸。APOE4突触膜含有这些EFA的缺陷，在糟糕的饮食条件下，随着时间的推移，这种缺陷逐渐减少。ApoE4突触缺陷在具有高可塑性的大脑区域更为普遍。与载脂蛋白4携带者和载脂蛋白2携带者相比，载脂蛋白4携带者存在固有的脑脂平衡缺陷，载脂蛋白E等位基因以共显性方式起作用。我们的研究提案的完成将为APOE4如何与AD风险增加相关提供答案。一种独特的动物模型将被测试其在描绘APOE依赖的突触完整性下降方面的有效性。解释载脂蛋白E在大脑中的功能的新机制将被阐明。

DESCRIPTION (provided by applicant): The human APOE4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE4 carriers. It has been proposed that apolipoprotein (apo) E functions to maintain synaptic integrity in the central nervous system during development and during remodeling and repair of neurons. Studies from our lab using a human apoE targeted replacement (TR) mouse model system provide supporting evidence for apoE's role in synaptic integrity. Young (7 month) apoE4 mice show significantly reduced excitatory synaptic activity and dendritic arborization compared to apoES mice, prior to any age-dependent markers of neuropathology. Collaborative studies with the age matched apoE4 mice show deficits in memory and hippocampal LTP compared to apoES mice. We plan to determine when the synaptic deficit begins and which brain regions are vulnerable to APOE4 synaptic deficits. We find significant reductions in specific phospholipid species (i.e. putative essential fatty acids (EFA)) in apoE4 hippocampus compared to apoES mice. These types of fatty acids are required for effective synaptic function. We plan to determine if other brain regions show similar reductions in essential fatty acids. We propose that the observed apoE4 synaptic deficits can be partly explained by alterations in cholesterol and fatty acid metabolism in synaptic membranes. Therefore, we wish to test the following hypotheses. We propose that APOE4 carriers are deficient in maintaining adequate levels of essential fatty acids required for synaptic plasticity, when exposed to an unhealthy diet. That APOE4 synaptic membrane contain a deficit in these EFA which gradually decrease over time under poor dietary conditions. APOE4 synaptic deficits are more prevalent in brain regions containing high plasticity. An inherent deficiency in brain lipid homeostasis exists in APOE4 carriers compared to APOES and APOE2 and that the APOE alleles act in a co-dominant fashion. Completion of our research proposal will provide answers to how APOE4 is linked to increased risk for AD. A unique animal model will be tested for its effectiveness in portraying APOE-dependent decline in synaptic integrity. Novel mechanisms to explain apoE's function in the brain will be elucidated.