APOE4 and Loss of Synaptic Integrity

描述（由申请人提供）：人类APOE4等位基因与早发年龄和阿尔茨海默病（AD）风险增加有关。早在阿尔茨海默病发病之前，APOE4携带者就可以识别出认知缺陷。载脂蛋白（apo） E在中枢神经系统的发育和神经元的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。幼龄（7个月）apoE4小鼠与apoES小鼠相比，兴奋性突触活性和树突状树杈明显减少，这比任何年龄依赖性神经病理学标志物都要早。与年龄匹配的apoE4小鼠的合作研究显示，与apoE4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易受APOE4突触缺陷的影响。我们发现，与载脂蛋白小鼠相比，apoE4海马中特定磷脂种类（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。我们计划确定大脑的其他区域是否也显示出类似的必需脂肪酸减少。我们提出观察到的apoE4突触缺陷可以部分解释为突触膜中胆固醇和脂肪酸代谢的改变。因此，我们希望检验以下假设。我们提出APOE4携带者在暴露于不健康饮食时，缺乏维持突触可塑性所需的必需脂肪酸的足够水平。APOE4突触膜在这些EFA中含有缺陷，在不良饮食条件下随着时间的推移逐渐减少。APOE4突触缺陷在具有高可塑性的大脑区域更为普遍。与APOES和APOE2相比，APOE4携带者存在固有的脑脂质稳态缺陷，并且APOE等位基因以共显性方式起作用。我们的研究计划的完成将提供APOE4如何与AD风险增加相关联的答案。一个独特的动物模型将测试其在描绘apoe依赖性突触完整性下降的有效性。新的机制来解释apoE在大脑中的功能将被阐明。

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.