2. Academic Validation
  3. Thymosin β4-derived peptides alleviate neuroinflammation and neurite atrophy in both in vitro models and in vivo 5 × FAD mice: A potential therapy for memory improvement in Alzheimer's disease

Thymosin β4-derived peptides alleviate neuroinflammation and neurite atrophy in both in vitro models and in vivo 5 × FAD mice: A potential therapy for memory improvement in Alzheimer's disease

  • Int Immunopharmacol. 2026 Feb 1:170:116097. doi: 10.1016/j.intimp.2025.116097.
Haiyan Ou 1,  Ruiye Chen 1,  Longjian Zhou 1,  Yi Zhang 1,  Shuai Zhao 2,  Zhiyou Yang 3
Affiliations

Affiliations

  • 1 College of Food Science and Technology, Shenzhen Institute of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Guangdong Ocean University, Zhanjiang 524088, China.
  • 2 College of Food Science and Technology, Shenzhen Institute of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Guangdong Ocean University, Zhanjiang 524088, China. Electronic address: [email protected].
  • 3 College of Food Science and Technology, Shenzhen Institute of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Guangdong Ocean University, Zhanjiang 524088, China. Electronic address: [email protected].
PMID: 41443105 DOI: 10.1016/j.intimp.2025.116097
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by neuroinflammation, neurite atrophy, and cognitive decline. This study explored the therapeutic potential of Thymosin β4 (Tβ4)-derived peptides (TB500 and Ac-SDKP) in mitigating AD-related neuropathology. Using the 5 × FAD mouse model and established in vitro AD cell systems, we evaluated the neuroprotective and anti-inflammatory effects of these peptides. In Aβ25-35-treated HT22 cells and primary cortical neurons, TB500 and Ac-SDKP significantly attenuated neurite atrophy, restored cell viability, and modulated the expression of apoptosis-related genes. In BV2 microglia assays, the peptides exhibited robust anti-inflammatory effects, as shown by suppressing lipopolysaccharide (LPS)-induced nitric oxide (NO) production, reducing expression of pro-inflammatory cytokines, and inhibiting M1 microglial polarization. In 5 × FAD mice, TB500 and Ac-SDKP ameliorated cognitive impairments, as evidenced by improved performance in the Morris water maze and novel object recognition tests. Immunohistochemical analyses revealed markedly reduced glial activation and neuronal Apoptosis in treated mice. Notably, the peptides restored axonal density in the perirhinal cortex and attenuated β-amyloid (Aβ) plaque-associated dystrophic neurites, though hippocampal Aβ burden remained unchanged. Transcriptomic profiling identified critical regulatory genes, including forkhead box B2 (Foxb2) and Olfactory Receptor, family 2, subfamily K, member 2 (Or2k2), and linked their neuroprotective effects to the modulation of Apoptosis and synaptic plasticity. Collectively, TB500 and Ac-SDKP exert multi-targeted efficacy against AD pathology by enhancing neuronal survival, suppressing neuroinflammation, and promoting axonal regeneration, thereby emerging as promising candidates for AD intervention.

Keywords

Ac-SDKP; Alzheimer's disease; Cognitive impairment; Neurite regeneration; TB500.

Figures
Products