| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Semi, Yuko Inui, Takashi Harada, Naoki Itakura, Masanori Kume, Satoshi Kubo, Takeya Azuma, Yasu-taka Kuwamura, Mitsuru Higashida, Shusaku Nakajima, Hidemitsu Kita, Akinori Takeuchi, Tadayoshi Kaneshige, Akihiro Yamaji, Ryoichi |
| Description |
Author Affiliation: Itakura M ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Nakajima H ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and hnakajima@vet.osakafu-u.ac.jp.); Kubo T ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Semi Y ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Kume S ( the Laboratories of Biological Macromolecules and.); Higashida S ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Kaneshige A ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Kuwamura M ( Laboratory of Veterinary Pathology, Osaka Prefecture University, Osaka 5988531 and.); Harada N ( Nutrition Chemistry, Osaka Prefecture University, Osaka 5998531, Japan.); Kita A ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Azuma YT ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.); Yamaji R ( Nutrition Chemistry, Osaka Prefecture University, Osaka 5998531, Japan.); Inui T ( the Laboratories of Biological Macromolecules and.); Takeuchi T ( From the Laboratory of Veterinary Pharmacology, Graduate School of Life and Environmental Sciences, and.) |
| Abstract |
Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by loss of neurons and formation of pathological extracellular deposits induced by amyloid-ß peptide (Aß). Numerous studies have established Aß 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 Aß amyloidogenesis and subsequent neuronal cell death both in vitro and in vivo. Co-incubation of Aß40 with small amounts of GAPDH aggregates significantly enhanced Aß40 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 Aß40 amyloidogenesis. In PC12 cells, GAPDH aggregates augmented Aß40-induced cell death, concomitant with disruption of mitochondrial membrane potential. Furthermore, mice injected intracerebroventricularly with Aß40 co-incubated with GAPDH aggregates exhibited Aß40-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/Aß co-aggregation and mitochondrial dysfunction were consistently detected in an age-dependent manner, and Aß aggregate formation was attenuated by GAPDH siRNA treatment. Thus, this study suggests that GAPDH aggregates accelerate Aß amyloidogenesis, subsequently leading to mitochondrial dysfunction and neuronal cell death in the pathogenesis of AD. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
43 |
| Volume Number |
290 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2015-10-23 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Alzheimer Disease Metabolism Amyloid Beta-Peptides Glyceraldehyde-3-Phosphate Dehydrogenases Biosynthesis Animals Mice Mice, Transgenic Microscopy, Atomic Force Mitochondria Physiology PC12 Cells Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
