Depletion of Paraoxonase 1 (Pon1) Dysregulates mTOR, Autophagy, and Accelerates Amyloid Beta Accumulation in Mice
| العنوان: | Depletion of Paraoxonase 1 (Pon1) Dysregulates mTOR, Autophagy, and Accelerates Amyloid Beta Accumulation in Mice |
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| المؤلفون: | Hieronim Jakubowski, Łukasz Witucki |
| المصدر: | Cells Volume 12 Issue 5 Pages: 746 |
| بيانات النشر: | MDPI AG, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | amyloid beta, autophagy, Pon1, Phf8, mTOR, N2a-APPswe cells, H4K20me1, homocysteine thiolactone, Pon1−/−5xFAD mouse model, General Medicine, APP |
| الوصف: | Paraoxonase 1 (PON1), a homocysteine (Hcy)-thiolactone detoxifying enzyme, has been associated with Alzheimer’s disease (AD), suggesting that PON1 plays an important protective role in the brain. To study the involvement of PON1 in the development of AD and to elucidate the mechanism involved, we generated a new mouse model of AD, the Pon1−/−xFAD mouse, and examined how Pon1 depletion affects mTOR signaling, autophagy, and amyloid beta (Aβ) accumulation. To elucidate the mechanism involved, we examined these processes in N2a-APPswe cells. We found that Pon1 depletion significantly downregulated Phf8 and upregulated H4K20me1; mTOR, phospho-mTOR, and App were upregulated while autophagy markers Bcln1, Atg5, and Atg7 were downregulated at the protein and mRNA levels in the brains of Pon1─/─5xFAD vs. Pon1+/+5xFAD mice. Pon1 depletion in N2a-APPswe cells by RNA interference led to downregulation of Phf8 and upregulation of mTOR due to increased H4K20me1-mTOR promoter binding. This led to autophagy downregulation and significantly increased APP and Aβ levels. Phf8 depletion by RNA interference or treatments with Hcy-thiolactone or N-Hcy-protein metabolites similarly increased Aβ levels in N2a-APPswe cells. Taken together, our findings define a neuroprotective mechanism by which Pon1 prevents Aβ generation. |
| وصف الملف: | application/pdf |
| تدمد: | 2073-4409 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::84fe1d74f74060a2354ef70d64807407 https://doi.org/10.3390/cells12050746 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....84fe1d74f74060a2354ef70d64807407 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20734409 |
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