Microglia Gravitate toward Amyloid Plaques Surrounded by Externalized Phosphatidylserine via TREM2.

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 (Aß) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aß) 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 Aß via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aß 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 Aß plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aß plaques in the context of the presence of ePtdSer during AD progression.

Electrophysiological insights with brain organoid models: A brief review.

Brain organoid is a three-dimensional (3D) tissue derived from stem cells such as induced pluripotent stem cells (iPSCs) embryonic stem cells (ESCs) that reflect real human brain structure. It replicates the complexity and development of the human brain, enabling studies of the human brain in vitro. With emerging technologies, its application is various, including disease modeling and drug screening. A variety of experimental methods have been used to study structural and molecular characteristics of brain organoids. However, electrophysiological analysis is necessary to understand their functional characteristics and complexity. Although electrophysiological approaches have rapidly advanced for monolayered cells, there are some limitations in studying electrophysiological and neural network characteristics due to the lack of 3D characteristics. Herein, electrophysiological measurement and analytical methods related to neural complexity and 3D characteristics of brain organoids are reviewed. Overall, electrophysiological understanding of brain organoids allows us to overcome limitations of monolayer in vitro cell culture models, providing deep insights into the neural network complex of the real human brain and new ways of disease modeling.