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Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis

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机构： [1]Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. [2]Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, 100053, China. [3]Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, 100053, China. [4]Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100053, China. [5]Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.

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关键词： Alzheimer’s disease Trofinetide Amyloid-β Cognitive impairment Neuroinflammation Apoptosis PPAR-γ Caspase-3

摘要：

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth factor 1 (IGF-1), has shown neuroprotective effects in various neurological disorders, but its role in AD remains unclear. Six-month-old APP/PS1 transgenic mice received intraperitoneal trofinetide for 2 months. Cognitive function was assessed using the Morris water maze (MWM) test. Immunohistochemistry (IHC) and immunofluorescence (IF) evaluated β-amyloid (Aβ) pathology, microglial activation, and neuronal loss. In vitro, BV2 microglial cells and HT22 hippocampal neurons were treated with trofinetide against AβO-induced cytotoxicity. Western blot (WB) was used to analyze inflammation and apoptosis-related proteins. Trofinetide significantly improved cognitive deficits, reduced Aβ plaque deposition, and decreased microglial activation and neuronal loss in APP/PS1 mice. In vitro, it rescued AβO-induced cytotoxicity, suppressed inflammatory cytokines (TNF-α, IL-6, IL-1) in BV2 cells, and inhibited apoptosis in HT22 cells. Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD.© 2025. The Author(s).

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出版当年[2025]版：

大类 | 2 区医学

小类 | 2 区神经科学

最新[2025]版：

大类 | 2 区医学

小类 | 2 区神经科学

第一作者：

第一作者机构： [1]Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.

通讯作者：

通讯机构： [1]Innovation Center for Neurological Disorders, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. [2]Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, 100053, China. [3]Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, 100053, China. [4]Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100053, China. [5]Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.

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