Zhong Ning, Scearce-Levie Kimberly, Ramaswamy Gayathri, Weisgraber Karl H
Gladstone Institute of Neurological Disease, The J. David Gladstone Institutes, San Francisco, CA, USA.
Alzheimers Dement. 2008 May;4(3):179-92. doi: 10.1016/j.jalz.2008.01.006.
Apolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms-domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4-associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock-in models.
We analyzed Arg-61 apoE mice, a gene-targeted model that selectively displays domain interaction.
The mice displayed age-dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin-1. Activation of dentate gyrus granule neurons increased Arc expression 3.5-fold in wildtype mice but only 2.3-fold in Arg-61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg-61 mice in the water-maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter 1 in the hippocampus. The level was reduced in Arg-61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg-61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair.
Domain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease.
载脂蛋白E4（apoE4）是阿尔茨海默病（AD）和其他神经退行性疾病的主要遗传风险因素，它具有三种结构和生物物理特性，使其与其他亚型区分开来——结构域相互作用、稳定性降低以及缺乏半胱氨酸。从机制和治疗的角度来看，评估它们对apoE4相关发病机制在AD中的影响的相对贡献很重要，但使用人类apoE转基因或基因敲入模型无法做到这一点。
我们分析了Arg-61 apoE小鼠，这是一种选择性显示结构域相互作用的基因靶向模型。
这些小鼠在新皮层和海马体中表现出与年龄相关的突触蛋白突触素损失，并且突触后神经连接蛋白-1水平较低。齿状回颗粒神经元的激活使野生型小鼠中的Arc表达增加3.5倍，但在Arg-61小鼠中仅增加2.3倍。突触蛋白的损失在水迷宫试验中导致Arg-61小鼠出现轻度记忆缺陷。由于突触完整性需要有效的谷氨酸摄取，我们测量了海马体中的星形胶质细胞谷氨酸转运体1。Arg-61小鼠中的该水平降低，表明星形胶质细胞对谷氨酸的摄取效率低下会导致慢性兴奋性毒性。与该模型中星形胶质细胞分泌的Arg-61 apoE减少一致，胆固醇分泌也减少了34%。这种减少也可能通过限制神经元修复所需胆固醇的可用性而导致突触缺陷。
在缺乏apoE4其他结构特征的情况下，结构域相互作用足以导致突触病理和功能性突触缺陷，这可能与星形胶质细胞功能障碍和神经元维持受损有关。针对结构域相互作用的治疗靶点可能会减弱apoE4在神经退行性疾病中的作用。
