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Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-?B-mediated BACE1 gene expression.

ABSTRACT: Amyloid-? (A?) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via ?-secretase (BACE1) and the ?-secretase complex. It has been proposed that the abnormal secretion and accumulation of A? 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 A?-induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on A? levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and A? production by decreasing BACE1 expression in vivo and in vitro. CO reduces A? levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor-kappa B (NF-?B). Consistent with the negative role of SIRT1 in the NF-?B 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-?B-mediated transcription of BACE1 induced by the cholesterol oxidation product 27-hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF-?B-mediated BACE1 transcription and consequently decreases A? production. Our study provides novel mechanisms by which CO reduces BACE1 expression and A? production and may be an effective agent for AD treatment.

SUBMITTER: Kim HJ

PROVIDER: S-EPMC6351829 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-κB-mediated BACE1 gene expression.

Kim Hyo Jeong HJ Joe Yeonsoo Y Chen Yingqing Y Park Gyu Hwan GH Kim Uh-Hyun UH Chung Hun Taeg HT

Aging cell 20181109 1

Amyloid-β (Aβ) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β-secretase (BACE1) and the γ-secretase complex. It has been proposed that the abnormal secretion and accumulation of Aβ 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 ...[more]

PMID: 30411846

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Project description:Mutations in amyloid ? precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, ?-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid ? protein (A?) production, and predominantly at major Glu11 site to generate C89, resulting in truncated A? production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential ?-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate A?, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT ?-site APP cleaving enzyme 1 (BACE1) is essential for amyloid ? protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid ? precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited ?-secretase cleavage of the mutant C99 to generate amyloid ? protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

Dataset Information

Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-?B-mediated BACE1 gene expression.

Publications

Carbon monoxide attenuates amyloidogenesis via down-regulation of NF-κB-mediated BACE1 gene expression.

Similar Datasets

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