title: Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.
abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-β peptide (Aβ). Numerous studies have established Aβ amyloidogenesis as a hallmark of AD pathogenesis, particularly with respect to mitochondrial dysfunction. We have previously shown that glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) forms amyloid-like aggregates upon exposure to oxidative stress and that these aggregates contribute to neuronal cell death. Here, we report that GAPDH aggregates accelerate Aβ amyloidogenesis and subsequent neuronal cell death both in vitro and in vivo. Co-incubation of Aβ40 with small amounts of GAPDH aggregates significantly enhanced Aβ40 amyloidogenesis, as assessed by in vitro thioflavin-T assays. Similarly, structural analyses using Congo red staining, circular dichroism, and atomic force microscopy revealed that GAPDH aggregates induced Aβ40 amyloidogenesis. In PC12 cells, GAPDH aggregates augmented Aβ40-induced cell death, concomitant with disruption of mitochondrial membrane potential. Furthermore, mice injected intracerebroventricularly with Aβ40 co-incubated with GAPDH aggregates exhibited Aβ40-induced pyramidal cell death and gliosis in the hippocampal CA3 region. These observations were accompanied by nuclear translocation of apoptosis-inducing factor and cytosolic release of cytochrome c from mitochondria. Finally, in the 3×Tg-AD mouse model of AD, GAPDH/Aβ co-aggregation and mitochondrial dysfunction were consistently detected in an age-dependent manner, and Aβ aggregate formation was attenuated by GAPDH siRNA treatment. Thus, this study suggests that GAPDH aggregates accelerate Aβ amyloidogenesis, subsequently leading to mitochondrial dysfunction and neuronal cell death in the pathogenesis of AD.
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Masanori
authors.initials: M
authors.lastname: Itakura
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and hnakajima@vet.osakafu-u.ac.jp.
authors.forename: Hidemitsu
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Takeya
authors.initials: T
authors.lastname: Kubo
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Semi
authors.affiliation: the Laboratories of Biological Macromolecules and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kume
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Higashida
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kaneshige
authors.affiliation: Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka 5988531 and.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kuwamura
authors.affiliation: Nutrition Chemistry, Osaka Prefecture University, Osaka 5998531, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kita
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Yasu-Taka
authors.initials: YT
authors.lastname: Azuma
authors.affiliation: Nutrition Chemistry, Osaka Prefecture University, Osaka 5998531, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
authors.affiliation: the Laboratories of Biological Macromolecules and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Inui
authors.affiliation: From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Takeuchi
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D008928:Mitochondria / Q000502:physiology; D016716:PC12 Cells; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
keywords: Alzheimer disease; GAPDH; amyloid-beta (AB); mitochondrial dysfunction; mitochondrial membrane potential; protein aggregation; transgenic mice