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.
This study investigated whether two peptides derived from Thymosin β4 (Tβ4) — TB500 and Ac-SDKP — could reduce Alzheimer's disease (AD)-related pathology using both cell-based and animal models. In vitro, the peptides were tested in Aβ25-35-treated HT22 neuronal cells and primary cortical neurons, where they were found to reduce neurite atrophy, restore cell viability, and modulate apoptosis-related gene expression. In BV2 microglia, the peptides suppressed LPS-induced nitric oxide production, reduced pro-inflammatory cytokines, and inhibited M1 microglial polarization. In the 5×FAD transgenic mouse model of AD, treated animals showed improved performance on the Morris water maze and novel object recognition tests compared to untreated counterparts. Immunohistochemical analyses indicated reduced glial activation and neuronal apoptosis in treated mice, along with restored axonal density in the perirhinal cortex. However, hippocampal amyloid-β plaque burden was not significantly changed. Transcriptomic profiling highlighted genes such as Foxb2 and Or2k2 as potentially relevant to the observed neuroprotective effects. Key limitations include the exclusive use of preclinical models (no human data), reliance on a single transgenic mouse strain, and the need for further mechanistic validation. No human trials were conducted.
Why this grade: All experiments were conducted in cell culture systems and a transgenic mouse model (5×FAD) with no human subjects, placing this firmly in the preclinical domain despite using both in vitro and in vivo approaches.
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.
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