Publication
Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.
Park Jong-Chan, Han Jong Won, Lee Woochan, Kim Jieun, Lee Sang-Eun, Lee Dongjoon, Choi Hayoung, Han Jihui, Kang You Jung, Diep Yen N, Cho Hansang, Kang Rian, Yu Won Jong, Lee Jean, Choi Murim, Im Sun-Wha, Kim Jong-Il, Mook-Jung Inhee
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