APOE4 and Loss of Synaptic Integrity

描述（由申请人提供）：人APOE4等位基因与阿尔茨海默病（AD）的早期发病年龄和风险增加相关。早在AD发病前，APOE4携带者就可发现认知缺陷。已经提出，载脂蛋白（apo）E的功能，以维持突触的完整性在中枢神经系统在发育过程中，并在重塑和修复的神经元。我们实验室使用人类apoE靶向替代（TR）小鼠模型系统的研究为apoE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（7个月）的apoE4小鼠在出现任何年龄依赖性神经病理学标志物之前显示出显著降低的兴奋性突触活性和树突状分支。与apoES小鼠相比，年龄匹配的apoE4小鼠的协作研究显示记忆和海马LTP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apoE4海马中的特定磷脂种类（即推定的必需脂肪酸（EFA））与apoES小鼠相比显著减少。这些类型的脂肪酸是有效的突触功能所必需的。我们计划确定其他大脑区域是否显示出类似的必需脂肪酸减少。我们认为，所观察到的apoE4突触缺陷可以部分解释突触膜中胆固醇和脂肪酸代谢的改变。因此，我们希望测试以下假设。我们认为，APOE4载体缺乏维持足够水平的必需脂肪酸所需的突触可塑性，当暴露于不健康的饮食。APOE4突触膜含有这些EFA的缺陷，这些EFA在不良饮食条件下随着时间的推移逐渐减少。APOE4突触缺陷在含有高可塑性的大脑区域中更普遍。与APOES和APOE 2相比，APOE 4携带者存在脑脂质稳态的固有缺陷，并且APOE等位基因以共显性方式起作用。我们研究提案的完成将为APOE 4如何与AD风险增加相关提供答案。将测试一种独特的动物模型在描绘突触完整性的APOE依赖性下降方面的有效性。新的机制来解释载脂蛋白E在大脑中的功能将得到阐明。

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.