GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-? accumulation and neuroinflammation in middle-aged Shugoshin 1 mice.

ABSTRACT: The cerebral amyloid-? 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-? 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-? accumulation was determined as 15-18 months of age (late middle age) in the Sgo1-/+ model. The amyloid-? accumulation was associated with unexpected GSK3?/? 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-? expression occurred with amyloid-? accumulation and was pronounced in the aged (24-month-old) Sgo1-/+ model mice. AD-relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and ?-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-? 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.

SUBMITTER: Rao CV 

PROVIDER: S-EPMC7576275 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature