KMID : 0620920230550092067
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Experimental & Molecular Medicine 2023 Volume.55 No. 9 p.2067 ~ p.2082
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Lactobacillus-derived extracellular vesicles counteract A¥â42-induced abnormal transcriptional changes through the upregulation of MeCP2 and Sirt1 and improve A¥â pathology in Tg-APP/PS1 mice
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Kwon Hye-Jin
Lee Eun-Hwa Park So-Young Park Jin-Young Hong Jin-Hwan Kim Eun-Kyung Shin Tae-Seop Kim Yoon-Keun Han Pyung-Lim
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Abstract
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Mounting evidence suggests that probiotics are beneficial for treating Alzheimer¡¯s disease (AD). However, the mechanisms by which specific probiotics modify AD pathophysiology are not clearly understood. In this study, we investigated whether Lactobacillus paracasei-derived extracellular vesicles (Lpc-EV) can directly act on neuronal cells to modify amyloid-beta (A¥â)-induced transcriptional changes and A¥â pathology in the brains of Tg-APP/PS1 mice. Lpc-EV treatment in HT22 neuronal cells counteracts A¥â-induced downregulation of Brain-derived neurotrophic factor (Bdnf), Neurotrophin 3 (Nt3), Nt4/5, and TrkB receptor, and reverses A¥â-induced altered expression of diverse nuclear factors, including the downregulation of Methyl-CpG binding protein 2 (Mecp2) and Sirtuin 1 (Sirt1). Systematic siRNA-mediated knockdown experiments indicate that the upregulation of Bdnf, Nt3, Nt4/5, and TrkB by Lpc-EV is mediated via multiple epigenetic factors whose activation converges on Mecp2 and Sirt1. In addition, Lpc-EV reverses A¥â-induced downregulation of the A¥â-degrading proteases Matrix metalloproteinase 2 (Mmp-2), Mmp-9, and Neprilysin (Nep), whose upregulation is also controlled by MeCP2 and Sirt1. Lpc-EV treatment restores the downregulated expression of Bdnf, Nt4/5, TrkB, Mmp-2, Mmp-9, and Nep; induces the upregulation of MeCP2 and Sirt1 in the hippocampus; alleviates A¥â accumulation and neuroinflammatory responses in the brain; and mitigates cognitive decline in Tg-APP/PS1 mice. These results suggest that Lpc-EV cargo contains a neuroactive component that upregulates the expression of neurotrophic factors and A¥â-degrading proteases (Mmp-2, Mmp-9, and Nep) through the upregulation of MeCP2 and Sirt1, and ameliorates A¥â pathology and cognitive deficits in Tg-APP/PS1 mice.
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KEYWORD
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Alzheimer¡Çs disease, Biological therapy
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