| First Author | Rao CV | Year | 2020 |
| Journal | Aging Cell | Volume | 19 |
| Issue | 10 | Pages | e13221 |
| PubMed ID | 32857910 | Mgi Jnum | J:296937 |
| Mgi Id | MGI:6469371 | Doi | 10.1111/acel.13221 |
| Citation | Rao CV, et al. (2020) GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-beta accumulation and neuroinflammation in middle-aged Shugoshin 1 mice. Aging Cell 19(10):e13221 |
| abstractText | The cerebral amyloid-beta accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late-onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1(-/+) ) mouse model, a model for mitotic cohesinopathy-genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid-beta in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid-beta accumulation was determined as 15-18 months of age (late middle age) in the Sgo1(-/+) model. The amyloid-beta accumulation was associated with unexpected GSK3alpha/beta inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3-Arc/Arg3.1 axis and the GSK3-Wnt axis. As observed in human AD brains, neuroinflammation with IFN-gamma expression occurred with amyloid-beta accumulation and was pronounced in the aged (24-month-old) Sgo1(-/+) model mice. AD-relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and beta-oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle-aged Sgo1(-/+) brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid-beta accumulation in the Sgo1(-/+) model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development. |
