2. Academic Validation
  3. Neuritin improves cognitive impairments in APP/PS1 Alzheimer's disease mice model by mitigating neuronal ferroptosis via PI3K/Akt activation

Neuritin improves cognitive impairments in APP/PS1 Alzheimer's disease mice model by mitigating neuronal ferroptosis via PI3K/Akt activation

  • Int J Biol Macromol. 2025 Feb 4:303:140662. doi: 10.1016/j.ijbiomac.2025.140662.
Dandan Song 1,  Fei Gui 2,  Guoxiang Li 3,  Shuai Zhuang 3,  Jiawei Sun 3,  Xiaohua Tan 4,  Chenglin Hong 5,  Jin Huang 6
Affiliations

Affiliations

  • 1 State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832003, PR China; Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China.
  • 2 Laboratory Animal Center, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China; The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, PR China.
  • 3 The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, PR China.
  • 4 Department of Preventive Medicine, School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang 311121, PR China. Electronic address: xiaohuatan@hznu.edu.cn.
  • 5 State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi, Xinjiang 832003, PR China. Electronic address: hcl_tea@shzu.edu.cn.
  • 6 The Key Laboratory of Xinjiang Endemic and Ethnic Diseases and Department of Biochemistry, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, PR China. Electronic address: huangjin623@163.com.
PMID: 39914536 DOI: 10.1016/j.ijbiomac.2025.140662
Abstract

The neurotrophic factor Neuritin is known to enhance cognitive capacity and to mitigate synaptic impairments in the APP/PS1 Alzheimer's disease (AD) mouse model, suggesting therapeutic potential for clinical treatment. However, the core molecular mechanisms remain elusive. Ferroptosis, a form of programmed cell death linked to iron dysregulation and oxidative stress, contributes to neurodegeneration in AD in part by accelerating Amyloid-β deposition and neurofibrillary tangle formation. Here we examined if Neuritin can mitigate cognitive decline and neural degeneration in AD model mice by suppressing Ferroptosis. Age-dependent cognitive decline was associated with Neuritin downregulation and increased Ferroptosis in the hippocampus. Intracerebroventricular injection of exogenous Neuritin mitigated spatial and fear learning deficits as well as neural oxidative stress, Apoptosis, and Ferroptosis in the hippocampus without causing deleterious side effects. Neuritin injection also upregulated the activity of NAD+ kinase (NADK), the Enzyme responsible for converting NAD to anti-ferroptotic NADPH, in the hippocampus of AD mice as well as in cultured hippocampal neurons. Reduced Neuritin expression in the hippocampus AD mice was associated with reduced phosphorylation (activation) of Akt (p-Akt), and Neuritin administration enhanced p-Akt expression in both HT22 cells and AD model mice. Conversely, blocking the PI3K/Akt pathway in HT22 cells reversed the Neuritin-induced increase in NADK activity and reduction in Ferroptosis, indicating that Neuritin protects neurons from AD-induced damage by enhancing NADK activity through the PI3K/Akt pathway. Collectively, our results support Neuritin upregulation as a potential therapeutic strategy for early-phase AD.

Keywords

Alzheimer's disease; Ferroptosis; Neuritin.

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