Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function.
Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function.
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DOI：
10.2174/1567205013666160401115127
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发表时间：
2016
影响因子：
2.1
通讯作者：
Rebeck GW
中科院分区：
文献类型：
--
作者：
Di Battista AM;Heinsinger NM;Rebeck GW
APOE-ε4是阿尔茨海默病（AD）最强的遗传风险因子，与淀粉样蛋白沉积水平增加和早期发病相关。最近的数据表明，AD的病理变化发生在临床症状之前几十年，这就提出了关于该疾病确切发病的问题。现在，在小鼠和人类中的方法的融合已经证明，APOE-ε4即使在没有严重AD病理变化的情况下也会影响正常的脑功能，即使是在生命的早期。表达APOE 4的正常小鼠具有任务特异性空间学习缺陷，以及减少的NMDAR依赖性信号传导和神经元中突触前和突触后隔室的结构变化，特别是在海马区。拥有APOE-ε4的年轻人在某些行为任务上比APOE-ε4阴性的人更熟练，功能性磁共振成像显示，APOE-ε4的遗传对内侧颞叶脑活动有特定的影响。这些发现表明，APOE-ε4的遗传导致大脑终身变化，可能与AD的晚期风险有关。本文综述了APOE-ε4影响脑神经化学、结构和功能的几种可能机制。
APOE-ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and is associated with an increase in the levels of amyloid deposition and an early age of onset. Recent data demonstrate that AD pathological changes occur decades before clinical symptoms, raising questions about the precise onset of the disease. Now a convergence of approaches in mice and humans has demonstrated that APOE-ε4 affects normal brain function even very early in life in the absence of gross AD pathological changes. Normal mice expressing APOE4 have task-specific spatial learning deficits, as well as reduced NMDAR-dependent signaling and structural changes to presynaptic and postsynaptic compartments in neurons, particularly in hippocampal regions. Young humans possessing APOE-ε4 are more adept than APOE-ε4 negative individuals at some behavioral tasks, and functional magnetic resonance imaging has shown that inheritance of APOE-ε4 has specific effects on medial temporal brain activities. These findings suggest that inheritance of APOE-ε4 causes life long changes to the brain that may be related to the late risk of AD. Several possible mechanisms of how APOE-ε4 could affect brain neurochemistry, structure, and function are reviewed.