Xu Wei, Tan Lan, Yu Jin-Tai
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
Mol Neurobiol. 2015 Aug;52(1):399-413. doi: 10.1007/s12035-014-8878-3. Epub 2014 Sep 4.
Alzheimer's disease (AD) is a highly heritable disease (with heritability up to 76%) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer's disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.
阿尔茨海默病（AD）是一种高度可遗传的疾病（遗传度高达76%），其易感性具有复杂的遗传特征，其中大规模全基因组关联研究（GWASs）指出磷脂酰肌醇结合网格蛋白组装蛋白（PICALM）基因是晚发性阿尔茨海默病（LOAD）发病的一个易感位点。在此，我们总结了PICALM的已知功能，并讨论了其基因多态性及其与LOAD相关的潜在生理效应。有力的数据表明，PICALM主要通过调节β淀粉样蛋白（Aβ）肽的产生、运输和清除来影响AD风险，但也讨论了其他不依赖Aβ的途径，包括tau蛋白病、突触功能障碍、脂质代谢紊乱、免疫失调和铁稳态破坏。最后，鉴于PICALM可能以多种方式促进AD的发生，靶向PICALM可能为AD治疗提供有前景的新途径。
