Glyceraldehyde-3-phosphate Dehydrogenase Aggregates Accelerate Amyloid-β Amyloidogenesis in Alzheimer Disease.
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.
['Itakura|Masanori|M|', 'Nakajima|Hidemitsu|H|', 'Kubo|Takeya|T|', 'Semi|Yuko|Y|', 'Kume|Satoshi|S|', 'Higashida|Shusaku|S|', 'Kaneshige|Akihiro|A|', 'Kuwamura|Mitsuru|M|', 'Harada|Naoki|N|', 'Kita|Akinori|A|', 'Azuma|Yasu-Taka|YT|', 'Yamaji|Ryoichi|R|', 'Inui|Takashi|T|', 'Takeuchi|Tadayoshi|T|']
D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D005987:Glyceraldehyde-3-Phosphate Dehydrogenases D006801:Humans D051379:Mice D008822:Mice, Transgenic D018625:Microscopy, Atomic Force D008928:Mitochondria D016716:PC12 Cells D051381:Rats
Alzheimer disease mitochondrial dysfunction GAPDH mitochondrial membrane potential amyloid-beta (AB) protein aggregation transgenic mice