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Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2
Jong-Chan Park1,2,3, Jong Won Han4, Woochan Lee4,5
1Department of Biophysics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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 (APPNL-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.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) on microglia clears amyloid plaques in Alzheimer's disease. Externalized phosphatidylserine from neurons accelerates this TREM2-mediated clearance, offering new therapeutic insights.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key in brain homeostasis, clearing cellular debris and pathogens.
- Triggering receptor expressed on myeloid cells 2 (TREM2) is vital for microglial phagocytosis.
- Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaque accumulation and microglial dysfunction.
Purpose of the Study:
- To elucidate the mechanism driving TREM2-mediated phagocytosis of Aβ plaques.
- To investigate the role of externalized phosphatidylserine (ePtdSer) in this process.
- To assess microglial phagocytic capacity in AD models with TREM2 dysfunction.
Main Methods:
- Utilized advanced 2D/3D/4D co-culture systems with engineered TREM2 loss-of-function mutations.
- Employed brain organoids, microglia, and assembloids for in vitro modeling.
- Analyzed microglia from sporadic (APOE4) and familial (APP/MAPT) AD mouse models.
Main Results:
- Identified ePtdSer from dystrophic neurons as an accelerator of Aβ clearance via TREM2.
- Demonstrated reduced TREM2 levels and impaired phagocytosis of ePtdSer-positive Aβ plaques in AD models.
- Confirmed TREM2's role in microglial phagocytosis of Aβ plaques in the presence of ePtdSer.
Conclusions:
- ePtdSer is a critical factor enhancing TREM2-mediated microglial phagocytosis of Aβ plaques.
- Dysfunctional TREM2 and reduced phagocytic activity in AD models contribute to Aβ pathology.
- Findings provide novel insights into TREM2-dependent mechanisms in AD progression.
