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RISS 인기검색어
- 검색키워드
- 저자 : ( Gahee Bahn ) (검색결과 3 건)
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Bahn, Gahee,Park, Jong-Sung,Yun, Ui Jeong,Lee, Yoon Jee,Choi, Yuri,Park, Jin Su,Baek, Seung Hyun,Choi, Bo Youn,Cho, Yoon Suk,Kim, Hark Kyun,Han, Jihoon,Sul, Jae Hoon,Baik, Sang-Ha,Lim, Jinhwan,Wakabay National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.25
<P><B>Significance</B></P><P>Considering that Alzheimer’s disease (AD) is a chronic disease progressing over a long period of time, even a slight increase of <I>BACE1</I> expression may have a profound effect on Aβ accumulation. We describe a previously unknown mechanism that negatively regulates <I>BACE1</I> and <I>BACE1-AS</I> expression and demonstrate its pivotal role in the progression of Aβ and Tau pathologies and cognitive impairment in two mouse models of AD. Given the recent failures of the clinical trials using enzymatic inhibitors of BACE1, it is critical to explore alternative approaches such as down-regulating <I>BACE1</I> and <I>BACE1-AS</I> transcription. Our finding that NRF2 negatively regulates BACE1 and BACE1-AS therefore suggests a potential for disease modification by NRF2-activating phytochemicals or synthetic small molecules in AD.</P><P>BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of <I>BACE1</I> and a <I>BACE1</I> mRNA-stabilizing antisense RNA (<I>BACE1-AS</I>) are elevated in the brains of AD patients, implicating that dysregulation of <I>BACE1</I> expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of <I>BACE1</I> and <I>BACE1-AS</I> through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of <I>BACE1</I> and <I>BACE1-AS</I> expression is independent of redox regulation. NRF2 activation decreases production of <I>BACE1</I> and <I>BACE1-AS</I> transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases <I>BACE1</I> and <I>BACE1-AS</I> expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.</P>
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Atf3 induction is a therapeutic target for obesity and metabolic diseases
Kim, Suji,Song, No-Joon,Bahn, Gahee,Chang, Seo-Hyuk,Yun, Ui Jeong,Ku, Jin-Mo,Jo, Dong-Gyu,Park, Kye Won Elsevier 2018 Biochemical and biophysical research communication Vol.504 No.4
<P><B>Abstract</B></P> <P>Activating transcription factor 3 (<I>Atf3</I>) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Atf3 knockout mice increases body weight and impaired glucose tolerance in high fat diet fed mice. </LI> <LI> Atf3 knockout mice increases body weight in chow diet fed aged mice. </LI> <LI> Sulfuretin, a phytochemical Atf3 iducer, requires Atf3 expression to prevent obesity. </LI> </UL> </P>
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Baek, Seung Hyun,Park, So Jung,Jeong, Jae In,Kim, Sung Hyun,Han, Jihoon,Kyung, Jae Won,Baik, Sang-Ha,Choi, Yuri,Choi, Bo Youn,Park, Jin Su,Bahn, Gahee,Shin, Ji Hyun,Jo, Doo Sin,Lee, Joo-Yong,Jang, Cho Society for Neuroscience 2017 The Journal of neuroscience Vol.37 No.20
<P>Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-beta(A beta) in neurons and neuropathology and cognitive functions in A beta precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in A beta-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and A beta deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in A beta-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.</P>
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