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

Abstract:

:The cerebral amyloid-β 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-β 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-β accumulation was determined as 15-18 months of age (late middle age) in the Sgo1-/+ model. The amyloid-β accumulation was associated with unexpected GSK3α/β 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-γ expression occurred with amyloid-β accumulation and was pronounced in the aged (24-month-old) Sgo1-/+ model mice. AD-relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and β-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-β 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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Rao CV,Farooqui M,Madhavaram A,Zhang Y,Asch AS,Yamada HY

doi

10.1111/acel.13221

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

e13221

issue

10

eissn

1474-9718

issn

1474-9726

journal_volume

19

pub_type

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