| First Author | Kim HJ | Year | 2019 |
| Journal | Aging Cell | Volume | 18 |
| Issue | 1 | Pages | e12864 |
| PubMed ID | 30411846 | Mgi Jnum | J:273257 |
| Mgi Id | MGI:6275762 | Doi | 10.1111/acel.12864 |
| Citation | Kim HJ, et al. (2019) Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-kappaB-mediated BACE1 gene expression. Aging Cell 18(1):e12864 |
| abstractText | Amyloid-beta (Abeta) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via beta-secretase (BACE1) and the gamma-secretase complex. It has been proposed that the abnormal secretion and accumulation of Abeta are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment. Previous studies indicated that carbon monoxide (CO), a product of heme oxygenase (HO)-1, protects against Abeta-induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on Abeta levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and Abeta production by decreasing BACE1 expression in vivo and in vitro. CO reduces Abeta levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor-kappa B (NF-kappaB). Consistent with the negative role of SIRT1 in the NF-kappaB activity, CO fails to evoke significant decrease in BACE1 expression in the presence of the SIRT1 inhibitor. Furthermore, CO attenuates elevation of BACE1 level in brains of 3xTg-AD mouse model as well as mice fed high-fat, high-cholesterol diets. CO reduces the NF-kappaB-mediated transcription of BACE1 induced by the cholesterol oxidation product 27-hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF-kappaB-mediated BACE1 transcription and consequently decreases Abeta production. Our study provides novel mechanisms by which CO reduces BACE1 expression and Abeta production and may be an effective agent for AD treatment. |
