title: ApoE-isoform-dependent cellular uptake of amyloid-β is mediated by lipoprotein receptor LR11/SorLA.
abstract: The formation of senile plaques composed of β-amyloid (Aβ) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aβ deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-β (Aβ) through the binding of Aβ to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of Aβ through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4>apoE3>apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled Aβ were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular Aβ into the recipient cells was most prominently accentuated when cocultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of Aβ mediated by LR11/SorLA.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Yajima
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tokutake
authors.affiliation: Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Koyama
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan; Center for Transdisciplinary Research, Niigata University, Niigata, Japan; Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kasuga
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tezuka
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan. Electronic address: ikeuchi@bri.niigata-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
mesh_terms: D000483:Alleles; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D018920:Coculture Techniques; D018076:DNA, Complementary / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010100:Oxygen / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D018076:DNA, Complementary; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse; D010100:Oxygen
keywords: Alzheimer’s disease; Apolipoprotein E; LR11/SorLA; β-Amyloid