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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Theranostics
2024
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/39431021/ |
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| author | Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk |
| author_facet | Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk |
| collection | PubMed - marine biology |
| contents | Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease. Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk Animals Alzheimer Disease Mice Disease Models, Animal Memory Disorders PPAR delta Humans Microglia Mice, Transgenic Male Mice, Inbred C57BL Neuroinflammatory Diseases Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) δ is a potential target for AD. However, its regulatory mechanisms and therapeutic potential in AD remain unclear. We aimed to investigate if the activation of PPARδ using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. We synthesized a novel PPARδ agonist, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Compound , the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of inhibited amyloid plaque deposition by suppressing the expression of neuronal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and reduced abnormal glial hyperactivation and inflammatory responses, resulting in improved learning and memory in the APP/PS1 mouse model of AD. We identified that specific activation of PPARδ provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPARδ as a promising drug target for treating AD. |
| format | Artículo científico |
| id | pubmed_39431021 |
| institution | PubMed |
| language | en |
| publishDate | 2024 |
| publisher | Theranostics |
| record_format | pubmed |
| spellingShingle | Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease. Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk Animals Alzheimer Disease Mice Disease Models, Animal Memory Disorders PPAR delta Humans Microglia Mice, Transgenic Male Mice, Inbred C57BL Neuroinflammatory Diseases Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease. Kim, Hyeon Jeong Kim, Haelee Song, Jaeyoung Hong, Jun Young Lee, Elijah Hwejin Londhe, Ashwini M Choi, Ji Won Park, Sun Jun Oh, Eunseok Yoon, Heeseok Hwang, Hoosang Hahn, Dongyup Jung, Kyungjin Kwon, Sugyeong Kadayat, Tara Man Ma, Min Jung Joo, Jeongmin Kim, Jina Bae, Jae Hyun Hwang, Hayoung Pae, Ae Nim Cho, Sung Jin Park, Jong-Hyun Chin, Jungwook Kang, Heonjoong Park, Ki Duk Animals Alzheimer Disease Mice Disease Models, Animal Memory Disorders PPAR delta Humans Microglia Mice, Transgenic Male Mice, Inbred C57BL Neuroinflammatory Diseases Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by neurotoxicity, excessive inflammation, and cognitive impairment. The peroxisome proliferator-activated receptor (PPAR) δ is a potential target for AD. However, its regulatory mechanisms and therapeutic potential in AD remain unclear. We aimed to investigate if the activation of PPARδ using a highly selective and potent agonist could provide an effective therapeutic strategy against AD. We synthesized a novel PPARδ agonist, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Compound , the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of inhibited amyloid plaque deposition by suppressing the expression of neuronal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), and reduced abnormal glial hyperactivation and inflammatory responses, resulting in improved learning and memory in the APP/PS1 mouse model of AD. We identified that specific activation of PPARδ provides therapeutic effects on multiple pathogenic phenotypes of AD, including neuroinflammation and amyloid deposition. Our findings suggest the potential of PPARδ as a promising drug target for treating AD. |
| title | Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease. |
| topic | Animals Alzheimer Disease Mice Disease Models, Animal Memory Disorders PPAR delta Humans Microglia Mice, Transgenic Male Mice, Inbred C57BL Neuroinflammatory Diseases |
| url | https://pubmed.ncbi.nlm.nih.gov/39431021/ |