Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice

  • Seung Sik Yoo (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Sun Mi Gu (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Kyung Tak Nam (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Jeong Soon Choi (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Yong Sun Lee (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • In Jun Yeo (Healthcare Convergence Educational Group for Infectious Disease Management, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University) ;
  • Ji Eun Yu (Department of Pharmacy, College of Pharmacy, Mokpo National University) ;
  • Sanghyeon Kim (Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive) ;
  • Dong Won Lee (National Institute of Food and Drug Safety Evaluation) ;
  • Hyeon Joo Ham (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Ju Young Chang (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Jaesuk Yun (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Dong Ju Son (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Sang-Bae Han (College of Pharmacy and Medical Research Center, Chungbuk National University) ;
  • Jin Tae, Hong (College of Pharmacy and Medical Research Center, Chungbuk National University)
  • Received : 2025.12.01
  • Accepted : 2026.03.16
  • Published : 2026.05.01
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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 depression-like 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.

Keywords

Acknowledgement

This work was financially supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2025-02273102), the Bio&Medical Technology Development Program of the NRF funded by the Korea government (MSIT) (No. RS-2024-00440787), and Basic Science Research Program through the NRF funded by the Ministry of Education (RS-2024-00460411).

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