Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice.
Overview
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, Republic of Korea
- Healthcare Convergence Educational Group for Infectious Disease Management, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea
- Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850, USA
- National Institute of Food and Drug Safety Evaluation, Cheongju 28159, Republic of Korea
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.
Reproduced under the paper's license (CC BY-NC), from the paper cited above.
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Data
Datasets cited
- geo:GSE1297, at NCBI GEO; found in the text, “Notch2 expression correlated with depression…”
Other data links
- ncbi.nlm.nih.gov/
geo , NCBI; found in the text, “Selection of Gene Expression Omnibus dataset…” - ncbi.nlm.nih.gov/
geo/ , NCBI; found in the text, “Differential Expression Analysis”geo2r
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 6 keywords, 3 funders, 94 references.
Cite
This paper
Yoo, S. S., Gu, S. M., Nam, K. T., Choi, J. S., Lee, Y. S., Yeo, I. J., Yu, J. E., Kim, S., Lee, D. W., Ham, H. J., Chang, J. Y., Yun, J., Son, D. J., Han, S.-B., & Hong, J. T. (2026). Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice. Biomolecules & therapeutics, 34(3), 544-555. https://
BibTeX
@article{yoo2026stress,
author = {Yoo, Seung Sik and Gu, Sun Mi and Nam, Kyung Tak and Choi, Jeong Soon and Lee, Yong Sun and Yeo, In Jun and Yu, Ji Eun and Kim, Sanghyeon and Lee, Dong Won and Ham, Hyeon Joo and Chang, Ju Young and Yun, Jaesuk and Son, Dong Ju and Han, Sang-Bae and Hong, Jin Tae},
title = {{Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice}},
journal = {Biomolecules \& therapeutics},
year = {2026},
month = apr,
volume = {34},
number = {3},
pages = {544--555},
publisher = {Korean Society of Applied Pharmacology},
issn = {1976-9148},
doi = {10.4062/
url = {https://
pmid = {42059026},
pmcid = {PMC13149050}
}
RIS
TY - JOUR
AU - Yoo, Seung Sik
AU - Gu, Sun Mi
AU - Nam, Kyung Tak
AU - Choi, Jeong Soon
AU - Lee, Yong Sun
AU - Yeo, In Jun
AU - Yu, Ji Eun
AU - Kim, Sanghyeon
AU - Lee, Dong Won
AU - Ham, Hyeon Joo
AU - Chang, Ju Young
AU - Yun, Jaesuk
AU - Son, Dong Ju
AU - Han, Sang-Bae
AU - Hong, Jin Tae
TI - Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice
T2 - Biomolecules & therapeutics
J2 - Biomol Ther (Seoul)
PY - 2026
DA - 2026/
VL - 34
IS - 3
SP - 544
EP - 555
SN - 1976-9148
PB - Korean Society of Applied Pharmacology
DO - 10.4062/
UR - https://
LA - en
ER -
CSL-JSON
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