EFhd2 is a novel amyloid protein associated with pathological tau in Alzheimer's disease

Abstract

EFhd2 is a conserved calcium-binding protein, abundant within the central nervous system. Previous studies identified EFhd2 associated with pathological forms of tau proteins in the tauopathy mouse model JNPL3, which expresses the human tauP301L mutant. This association was validated in human tauopathies, such as Alzheimer's disease (AD). However, the role that EFhd2 may play in tauopathies is still unknown. Here, we show that EFhd2 formed amyloid structures in vitro, a capability that is reduced by calcium ions. Electron microscopy (EM) analyses demonstrated that recombinant EFhd2 formed filamentous structures. EM analyses of sarkosyl-insoluble fractions derived from human AD brains also indicated that EFhd2 co-localizes with aggregated tau proteins and formed granular structures. Immunohistological analyses of brain slices demonstrated that EFhd2 co-localizes with pathological tau proteins in AD brains, confirming the co-aggregation of EFhd2 and pathological tau. Furthermore, EFhd2's coiled-coil domain mediated its self-oligomerization in vitro and its association with tau proteins in JNPL3 mouse brain extracts. The results demonstrate that EFhd2 is a novel amyloid protein associated with pathological tau proteins in AD brain and that calcium binding may regulate the formation of EFhd2's amyloid structures. Hence, EFhd2 may play an important role in the pathobiology of tau-mediated neurodegeneration. The calcium binding protein EFhd2 is a novel amyloid protein that co-aggregates with pathological tau proteins in Alzheimer's disease. EFhd2 is overexpressed in Alzheimer's disease brain and its coiled-coil domain mediates the association with tau proteins. The formation of EFhd2 oligomers may contribute to the aggregation of tau proteins, to either promote neuronal death or survival. This study further demonstrates that EFhd2 is a molecular factor involved in the pathobiology of tauopathies. © 2013 International Society for Neurochemistry.