School of Life and Environmental Sciences, Deakin University, Burwood, Victoria, Australia.
The Florey Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia.
J Neurochem. 2024 Sep;168(9):3284-3307. doi: 10.1111/jnc.16198. Epub 2024 Aug 12.
The strongest genetic risk factor for late-onset Alzheimer's disease (AD) is allelic variation of the APOE gene, with the following risk structure: ε4 > ε3 > ε2. The biochemical basis for this risk profile is unclear. Here, we reveal a new role for the APOE gene product, apolipoprotein E (ApoE) in regulating cellular copper homeostasis, which is perturbed in the AD brain. Exposure of ApoE target replacement (TR) astrocytes (immortalised astrocytes from APOE knock-in mice) to elevated copper concentrations resulted in exacerbated copper accumulation in ApoE4- compared to ApoE2- and ApoE3-TR astrocytes. This effect was also observed in SH-SY5Y neuroblastoma cells treated with conditioned medium from ApoE4-TR astrocytes. Increased intracellular copper levels in the presence of ApoE4 may be explained by reduced levels and delayed trafficking of the copper transport protein, copper-transporting ATPase 1 (ATP7A/Atp7a), potentially leading to impaired cellular copper export. This new role for ApoE in copper regulation lends further biochemical insight into how APOE genotype confers risk for AD and reveals a potential contribution of ApoE4 to the copper dysregulation that is a characteristic pathological feature of the AD brain.
载脂蛋白 E（ApoE）基因的等位基因变异是晚发性阿尔茨海默病（AD）最强的遗传风险因素，其风险结构为：ε4>ε3>ε2。这种风险特征的生化基础尚不清楚。在这里，我们揭示了 APOE 基因产物载脂蛋白 E（ApoE）在调节细胞铜稳态方面的新作用，AD 大脑中的铜稳态受到干扰。将 ApoE 靶向替换（TR）星形胶质细胞（来自 APOE 基因敲入小鼠的永生化星形胶质细胞）暴露于高浓度铜中，导致 ApoE4-与 ApoE2-和 ApoE3-TR 星形胶质细胞相比，铜积累加剧。在接受来自 ApoE4-TR 星形胶质细胞条件培养基处理的 SH-SY5Y 神经母细胞瘤细胞中也观察到这种效应。在存在 ApoE4 的情况下，细胞内铜水平升高可能是由于铜转运蛋白铜转运 ATP 酶 1（ATP7A/Atp7a）的水平降低和运输延迟所致，这可能导致细胞铜输出受损。ApoE 在铜调节中的这种新作用进一步深入了解了 APOE 基因型如何为 AD 带来风险，并揭示了 ApoE4 对 AD 大脑中特征性病理特征之一的铜失调的潜在贡献。
