The Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.
Easton Laboratories for Neurodegenerative Disease Research, UCLA, Los Angeles, CA, 90025, USA.
Mol Neurobiol. 2018 Jun;55(6):5243-5254. doi: 10.1007/s12035-017-0757-2. Epub 2017 Sep 6.
The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the putative transcriptional role of ApoE4 and propose a model of Alzheimer's disease that focuses on the transcriptional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease.
散发性阿尔茨海默病（AD）的主要遗传风险因素是载脂蛋白 E，ε4 等位基因（ApoE4），这是一种脂质结合和转运载体蛋白。AD 的一个未解之谜是，ApoE4 的存在如何引发这种与年龄相关的、目前无法治愈的神经退行性疾病。最近，我们发现 ApoE4 作为一种转录因子，与参与衰老和 AD 发病机制相关过程的基因的启动子结合。这些发现为 AD 和衰老提供了新的治疗策略，从而延长了人类的健康寿命，即无病和功能期。在这里，我们回顾了 ApoE4 的假定转录作用的影响和意义，并提出了一个以 ApoE4 的转录性质及其下游效应为重点的阿尔茨海默病模型，目的是使这些知识有助于确定 ApoE4 作为 AD、衰老和其他过程（如炎症和心血管疾病）的风险因素的作用。
