Lactobacillus-derived extracellular vesicles counteract Aβ42-induced abnormal transcriptional changes through the upregulation of MeCP2 and Sirt1 and improve Aβ pathology in Tg-APP/PS1 mice
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 (...
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Veröffentlicht in: | Experimental & molecular medicine 2023, 55(0), , pp.2067-2082 |
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Zusammenfassung: | 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 (Aβ)-induced transcriptional changes and Aβ pathology in the brains of Tg-APP/PS1 mice.
Lpc
-EV treatment in HT22 neuronal cells counteracts Aβ-induced downregulation of
Brain-derived neurotrophic factor (Bdnf)
,
Neurotrophin 3 (Nt3)
,
Nt4/5
, and
TrkB
receptor, and reverses Aβ-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 Aβ-induced downregulation of the Aβ-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 Aβ 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 Aβ-degrading proteases (
Mmp-2, Mmp-9
, and
Nep
) through the upregulation of MeCP2 and Sirt1, and ameliorates Aβ pathology and cognitive deficits in Tg-APP/PS1 mice.
Alzheimer’s disease: bacteria-derived vesicles help to combat neurodegeneration
Small molecular membrane-bound vesicles released by probiotic bacteria can help to counteract the negative effects of amyloid-beta (Aβ), a protein that clumps inside the brain and is associated with the progression of Alzheimer’s disease. A team led by Yoon-Keun Kim from MD Healthcare Inc. and Pyung-Lim Han from Ewha Womans University, both in Seoul, South Korea, showed that these molecular packets — known as extracellular vesicles and derived from Lactobacillus bacteria found in the mouth and gut — can mitigate against Aβ-induced changes in gene expression in mouse neurons. By delivering neuroactiv |
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ISSN: | 2092-6413 1226-3613 2092-6413 |
DOI: | 10.1038/s12276-023-01084-z |