박민희 (경북대학교 의과대학)

한빛사논문

조회2,559

경북대학교 의과대학

CV File 173 kb

Proc. Natl. Acad. Sci. USA, First published November 4, 2019 | https://doi.org/10.1073/pnas.1916318116 N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

Min Hee Park^a,b,c, Misun Lee^d,e, Geewoo Nam^e, Mingeun Kim^d, Juhye Kang^d, Byung Jo Choi^a,f, Min Seock Jeong^a,f, Kang Ho Park^a,b,c, Wan Hui Han^a,b,c, Eunyoung Tak^g,h, Min Sun Kim^g,h, Juri Lee^d, Yuxi Linⁱ, Young-Ho Lee^i,j,k, Im-Sook Song^l, Min-Koo Choi^m, Joo-Yong Lee^g,h, Hee Kyung Jin^a,f,1, Jae-sung Bae^a,b,c,1, and Mi Hee Lim^d,1

^aKyungpook National University Alzheimer’s Disease Research Institute, Kyungpook National University, 41566 Daegu, Republic of Korea; ^bDepartment of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, 41944 Daegu, Republic of Korea;^c Department of Biomedical Science, BK21 Plus Kyungpook National University Biomedical Convergence Program, Kyungpook National University, 41944 Daegu, Republic of Korea; ^dDepartment of Chemistry, Korea Advanced Institute of Science and Technology, 34141 Daejeon, Republic of Korea;^e Department of Chemistry, Ulsan National Institute of Science and Technology, 44919 Ulsan, Republic of Korea; ^fDepartment of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, 41566 Daegu, Republic of Korea; ^g Asan Institute for Life Sciences, Asan Medical Center, 05505 Seoul, Republic of Korea; ^h Department of Convergence Medicine, University of Ulsan College of Medicine, 05505 Seoul, Republic of Korea;ⁱ Protein Structure Group, Korea Basic Science Institute, Ochang, 28199 Cheongju, Chungbuk, Republic of Korea; ^j Neurovascular Research Group, Korea Brain Research Institute, 41068 Daegu, Republic of Korea; ^k Bio-Analytical Science, University of Science and Technology, 34113 Daejeon, Republic of Korea; ^lCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, 41566 Daegu, Republic of Korea; and ^m College of Pharmacy, Dankook University, 31116 Cheon-an, Republic of Korea

¹To whom correspondence may be addressed.

Abstract

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

small molecule, antineuroinflammation, microglial phagocytosis, amyloid-β clearance, cognitive function

논문정보

형식Research article
게재일2019년 11월 (BRIC 등록일 2019-11-07)
연구진국내 연구진
분야 생명과학 > 생화학

댓글 작성 로그인

CV 열람하기

연락처 보기