Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice
10.4062/biomolther.2025.246
- Author:
Seung Sik YOO
1
;
Sun Mi GU
;
Kyung Tak NAM
;
Jeong Soon CHOI
;
Yong Sun LEE
;
In Jun YEO
;
Ji Eun YU
;
Sanghyeon KIM
;
Dong Won LEE
;
Hyeon Joo HAM
;
Ju Young CHANG
;
Jaesuk YUN
;
Dong Ju SON
;
Sang-Bae HAN
;
Jin Tae HONG
Author Information
1. College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Republic of Korea
- Publication Type:Original Article
- From:Biomolecules & Therapeutics
2026;34(3):544-555
- CountryRepublic of Korea
- Language:English
-
Abstract:
Alzheimer’s disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depressionlike behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer’s disease and depression.Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.
