Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease

Hyeon Jeong Kim; Haelee Kim; Jaeyoung Song; Jun Young Hong; Elijah Hwejin Lee; Ashwini M. Londhe; Ji Won Choi; Sun Jun Park; Eunseok Oh; Heeseok Yoon; Hoosang Hwang; Dongyup Hahn; Kyungjin Jung; Sugyeong Kwon; Tara Man Kadayat; Min Jung Ma; Jeongmin Joo; Jina Kim; Jae Hyun Bae; Hayoung Hwang; Ae Nim Pae; Sung Jin Cho; Jong Hyun Park; Jungwook Chin; Heonjoong Kang; Ki Duk Park

doi:10.7150/thno.96707

Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease

Hyeon Jeong Kim, Haelee Kim, Jaeyoung Song, Jun Young Hong, Elijah Hwejin Lee, Ashwini M. Londhe, Ji Won Choi, Sun Jun Park, Eunseok Oh, Heeseok Yoon, Hoosang Hwang, Dongyup Hahn, Kyungjin Jung, Sugyeong Kwon, Tara Man Kadayat, Min Jung Ma, Jeongmin Joo, Jina Kim, Jae Hyun Bae, Hayoung HwangAe Nim Pae, Sung Jin Cho, Jong Hyun Park, Jungwook Chin, Heonjoong Kang, Ki Duk Park

School of Food Science & Biotechnology

Research output: Contribution to journal › Article › peer-review

Abstract

Rationale: 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. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a 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. Conclusion: 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.

Original language	English
Pages (from-to)	6088-6108
Number of pages	21
Journal	Theranostics
Volume	14
Issue number	16
DOIs	https://doi.org/10.7150/thno.96707
State	Published - 2024

Keywords

Alzheimer’s disease
BACE1
PPARδ agonist
anti-inflammation
glial activation

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10.7150/thno.96707

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Kim, H. J., Kim, H., Song, J., Hong, J. Y., Lee, E. H., Londhe, A. M., Choi, J. W., Park, S. J., Oh, E., Yoon, H., Hwang, H., Hahn, D., Jung, K., Kwon, S., Kadayat, T. M., Ma, M. J., Joo, J., Kim, J., Bae, J. H., ... Park, K. D. (2024). Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease. Theranostics, 14(16), 6088-6108. https://doi.org/10.7150/thno.96707

@article{1634e903a8ab40dc96cfcf6cc2e2b104,

title = "Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease",

abstract = "Rationale: 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. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a 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. Conclusion: 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.",

keywords = "Alzheimer{\textquoteright}s disease, BACE1, PPARδ agonist, anti-inflammation, glial activation",

author = "Kim, {Hyeon Jeong} and Haelee Kim and Jaeyoung Song and Hong, {Jun Young} and Lee, {Elijah Hwejin} and Londhe, {Ashwini M.} and Choi, {Ji Won} and Park, {Sun Jun} and Eunseok Oh and Heeseok Yoon and Hoosang Hwang and Dongyup Hahn and Kyungjin Jung and Sugyeong Kwon and Kadayat, {Tara Man} and Ma, {Min Jung} and Jeongmin Joo and Jina Kim and Bae, {Jae Hyun} and Hayoung Hwang and Pae, {Ae Nim} and Cho, {Sung Jin} and Park, {Jong Hyun} and Jungwook Chin and Heonjoong Kang and Park, {Ki Duk}",

note = "Publisher Copyright: {\textcopyright} The author(s).",

year = "2024",

doi = "10.7150/thno.96707",

language = "English",

volume = "14",

pages = "6088--6108",

journal = "Theranostics",

issn = "1838-7640",

publisher = "Ivyspring International Publisher",

number = "16",

}

Kim, HJ, Kim, H, Song, J, Hong, JY, Lee, EH, Londhe, AM, Choi, JW, Park, SJ, Oh, E, Yoon, H, Hwang, H, Hahn, D, Jung, K, Kwon, S, Kadayat, TM, Ma, MJ, Joo, J, Kim, J, Bae, JH, Hwang, H, Pae, AN, Cho, SJ, Park, JH, Chin, J, Kang, H & Park, KD 2024, 'Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease', Theranostics, vol. 14, no. 16, pp. 6088-6108. https://doi.org/10.7150/thno.96707

TY - JOUR

T1 - Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease

AU - Kim, Hyeon Jeong

AU - Kim, Haelee

AU - Song, Jaeyoung

AU - Hong, Jun Young

AU - Lee, Elijah Hwejin

AU - Londhe, Ashwini M.

AU - Choi, Ji Won

AU - Park, Sun Jun

AU - Oh, Eunseok

AU - Yoon, Heeseok

AU - Hwang, Hoosang

AU - Hahn, Dongyup

AU - Jung, Kyungjin

AU - Kwon, Sugyeong

AU - Kadayat, Tara Man

AU - Ma, Min Jung

AU - Joo, Jeongmin

AU - Kim, Jina

AU - Bae, Jae Hyun

AU - Hwang, Hayoung

AU - Pae, Ae Nim

AU - Cho, Sung Jin

AU - Park, Jong Hyun

AU - Chin, Jungwook

AU - Kang, Heonjoong

AU - Park, Ki Duk

PY - 2024

Y1 - 2024

N2 - Rationale: 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. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a 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. Conclusion: 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.

AB - Rationale: 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. Methods: We synthesized a novel PPARδ agonist, 5a, containing a selenazole group and determined the X-ray crystal structure of its complex with PPARδ. The drug-like properties of 5a were assessed by analyzing cytochrome P450 (CYP) inhibition, microsomal stability, pharmacokinetics, and mutagenicity. We investigated the anti-inflammatory effects of 5a using lipopolysaccharide (LPS)-stimulated BV-2 microglia and neuroinflammatory mouse model. The therapeutic efficacy of 5a was evaluated in AD mice with scopolamine-induced memory impairment and APP/PS1 by analyzing cognitive function, glial reactivity, and amyloid pathology. Results: Compound 5a, the most potent and selective PPARδ agonist, was confirmed to bind hPPARδ in a complex by X-ray crystallographic analysis. PPARδ activation using 5a showed potent anti-inflammatory effects in activated glial cells and mouse model of neuroinflammation. Administration of 5a 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. Conclusion: 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.

KW - Alzheimer’s disease

KW - BACE1

KW - PPARδ agonist

KW - anti-inflammation

KW - glial activation

UR - http://www.scopus.com/inward/record.url?scp=85205142230&partnerID=8YFLogxK

U2 - 10.7150/thno.96707

DO - 10.7150/thno.96707

M3 - Article

C2 - 39431021

AN - SCOPUS:85205142230

SN - 1838-7640

VL - 14

SP - 6088

EP - 6108

JO - Theranostics

JF - Theranostics

IS - 16

ER -

Highly potent and selective PPARδ agonist reverses memory deficits in mouse models of Alzheimer's disease

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