Impaired cellular copper regulation in the presence of ApoE4

Abstract

AbstractThe 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.image