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  3. Neuronal GSK3β Protects Against Amyloid Pathology by Regulating APP Degradation

Neuronal GSK3β Protects Against Amyloid Pathology by Regulating APP Degradation

  • FASEB J. 2025 Nov 30;39(22):e71267. doi: 10.1096/fj.202502996R.
Yizhi Zhang 1,  Yajie Zhang 1,  Chenyi Ge 1,  Yang Liu 2 3,  Zhiye Wang 2 3,  Guiquan Chen 1 2
Affiliations

Affiliations

  • 1 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China.
  • 2 Suqian Scientific Research Institute of Nanjing University Medical School, Nanjing University, Nanjing, China.
  • 3 Department of Neurology, Meishan Hospital of Nanjing, Nanjing, China.
PMID: 41277295 DOI: 10.1096/fj.202502996R
Abstract

Glycogen synthase kinase 3β (GSK3β) exhibits dysregulated activity in Alzheimer's disease (AD), yet its cell type-specific roles in driving disease pathogenesis remain poorly understood. To explore the neuronal role of GSK3β in β-amyloid (Aβ) pathogenesis, we conditionally deleted Gsk3β in 5 × FAD mice using CaMKIIα-Cre-mediated recombination. Neuronal Gsk3β deletion exacerbated AD pathology, including increased Aβ deposition, pronounced gliosis, and enhanced neuroinflammatory responses. Loss of GSK3β impaired amyloid precursor protein (APP) degradation, leading to its accumulation and subsequent Aβ overproduction. These findings identify neuronal GSK3β as a critical modulator of APP turnover and Aβ pathology, revealing a protective role against AD progression. These findings suggest that broad inhibition of GSK3β may not be an optimal therapeutic strategy for AD, highlighting the importance of cell type-specific targeting.

Keywords

Alzheimer's disease; GSK3β; amyloid precursor protein; neuroinflammation; protein degradation.

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