title: 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 tau(P301L) 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.
authors: Department of Biology, College of Natural Sciences, University of Puerto Rico, San Juan, Puerto Rico.
authors: Yancy
authors: Y
authors: Ferrer-Acosta
authors: Eva N
authors: EN
authors: Rodríguez-Cruz
authors: François
authors: F
authors: Orange
authors: Hector
authors: H
authors: De Jesús-Cortés
authors: Bismark
authors: B
authors: Madera
authors: Jaime
authors: J
authors: Vaquer-Alicea
authors: Juan
authors: J
authors: Ballester
authors: Maxime J-F
authors: MJ
authors: Guinel
authors: George S
authors: GS
authors: Bloom
authors: Irving E
authors: IE
authors: Vega
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D058227:Amyloidogenic Proteins; D002135:Calcium-Binding Proteins; C502299:EFHD2 protein, human; C530752:EFHD2 protein, mouse; D016875:tau Proteins