Mutations in the β-amyloid precursor protein in familial Alzheimer’s disease increase Aβ oligomer production in cellular models
Yoichi Ohshima,
Katsutoshi Taguchi,
Ikuko Mizuta,
Masaki Tanaka,
Takami Tomiyama,
Fuyuki Kametani,
Chihiro Yabe-Nishimura,
Toshiki Mizuno,
Takahiko Tokuda
Affiliations
Yoichi Ohshima
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Katsutoshi Taguchi
Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Ikuko Mizuta
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Masaki Tanaka
Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Takami Tomiyama
Department of Neuroscience, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
Fuyuki Kametani
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Chihiro Yabe-Nishimura
Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Toshiki Mizuno
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Takahiko Tokuda
Department of Neurology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602-8566, Japan
Soluble oligomers of amyloid-β (Aβ) peptides (AβOs) contribute to neurotoxicity in Alzheimer’s disease (AD). However, it currently remains unknown whether an increase in AβOs is the common phenotype in cellular and animal models. Furthermore, it has not yet been established whether experimental studies conducted using models overexpressing mutant genes of the amyloid precursor protein (APP) are suitable for investigating the underlying molecular mechanism of AD. We herein employed the Flp-In™ T-REx™-293 (T-REx 293) cellular system transfected with a single copy of wild-type, Swedish-, Dutch-, or London-type APP, and quantified the levels of Aβ monomers (Aβ1-40 and Aβ1-42) and AβOs using an enzyme-linked immunosorbent assay (ELISA). The levels of extracellular AβOs were significantly higher in Dutch- and London-type APP-transfected cells than in wild-type APP-transfected cells. Increased levels were also observed in Swedish-type APP-transfected cells. On the other hand, intracellular levels of AβOs were unaltered among wild-type and mutant APP-transfected cells. Intracellular levels of Aβ monomers were undetectable, and no common abnormality was observed in their extracellular levels or ratios (Aβ1-42/Aβ1-40) among the cells examined. We herein demonstrated that increased levels of extracellular AβOs are the common phenotype in cellular models harboring different types of APP mutations. Our results suggest that extracellular AβOs play a key role in the pathogenesis of AD.
