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서울대학교 의과대학

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Adv. Sci., Jul 09 2024, | https://doi.org/10.1002/advs.202400064 Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2

Jong-Chan Park ^{1 2 3}^†, Jong Won Han ⁴^†, Woochan Lee ^{4 5}, Jieun Kim ⁴, Sang-Eun Lee ^{6 7 8 9}, Dongjoon Lee ⁴, Hayoung Choi ⁴, Jihui Han⁴, You Jung Kang ^{1 2}, Yen N Diep ^{1 2 10}, Hansang Cho ^{1 2 10}, Rian Kang^{2 3}, Won Jong Yu^{2 3}, Jean Lee ¹¹, Murim Choi ¹¹, Sun-Wha Im ¹², Jong-Il Kim ^{5 11 13 14}, Inhee Mook-Jung ^{4 15 *}

¹Department of Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

²Institute of Quantum Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

³Department of Metabiohealth, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

⁴Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

⁵Genome Medicine Institute, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea.

⁶Department of Physiology and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

⁷BK21 FOUR Biomedical Science Program, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

⁸UK Dementia Research Institute, Institute of Neurology, University College London, Gower Street, London, WC1E 6BT, UK.

⁹Neuroscience Research Institute, Seoul National University Medical Research Center, Seoul, 03080, Republic of Korea.

¹⁰Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

¹¹Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

¹²Department of Biochemistry and Molecular Biology, Kangwon National University School of Medicine, Gangwon, Seoul, 24341, Republic of Korea.

¹³Cancer Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.

¹⁴Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

¹⁵Convergence Dementia Research Center, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.

^*Corresponding author: correspondence to Inhee Mook-Jung
^†J.-C.P. and J.W.H. contributed equally to this work.

Abstract

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APP^NL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aβ plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-10)
연구진국내(교신)+국외 연구진
분야 의약학 > 신경의학

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