신효정 (충남대학교)

한빛사논문

조회288

신효정Hyo Jung Shin

충남대학교

Mol. Neurodegener., Mar 16 2024, 19 (1) | https://doi.org/10.1186/s13024-024-00715-x Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer's disease

Hyo Jung Shin^1,2, In Soo Kim^3,4, Seung Gyu Choi^1,2, Kayoung Lee^1,3,5, Hyewon Park^1,3, Juhee Shin^1,3, Dayoung Kim¹, Jaewon Beom⁵, Yoon Young Yi⁶, Deepak Prasad Gupta⁷, Gyun Jee Song^7,8, Won‑Suk Chung⁹, C. Justin Lee^10,11 and Dong Woon Kim^1,2,3,12*

¹Department of Anatomy and Cell Biology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.

²Brain Research Institute, Chungnam National University College of Medicine, Daejeon, Republic of Korea.

³Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea.

⁴Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.

⁵Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

⁶Department of Pediatrics, College of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.

⁷Department of Medicine, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon‑Do, Republic of Korea.

⁸Translational Brain Research Center, International St. Mary’s Hospital, Catholic Kwandong University, Incheon, Republic of Korea.

⁹Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

¹⁰Center for Glia–Neuron Interaction, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.

¹¹Center for Cognition and Sociality, Institute for Basic Science, Daejeon, Republic of Korea.

¹²Department of Oral Anatomy and Developmental Biology, College of Dentistry Kyung Hee University, Seoul, Republic of Korea.

*Correspondence: Dong Woon Kim

Abstract

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16 ^ink4a), a cell cycle factor related to aging. We found that p16 ^ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16 ^ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16 ^ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-18)
연구진국내 연구진
분야 바이오·의료융합 > 뇌인지과학

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