111年9月14日（三）12：30於3樓合心會議室舉辦「研究發想會」，由Stanford University 博士後研究員 蔡伯宜博士

主講「為什麼有些人不容易得阿茲海默症：微膠細胞microglia 上的保護性基因突變」

本次講座摘要：

Alzheimer’s disease (AD) is characterized by robust microgliosis triggered by amyloid plaque deposition. Recent studies have identified many genetic risk variants that are predominately expressed in microglia. Among these risk genes is phospholipase C gamma 2 (PLCG2), a critical regulatory hub for immune signaling. Importantly, missense variants in PLCG2 are associated with altered AD risk. A hypermorphic
P522R variant of PLCG2 has been reported to be protective against AD, and we have identified a novel variant associated with elevated AD risk encoding the less active M28L variant. However, the underlying mechanisms whereby PLCG2 variants alter microglial biology and disease pathology remains unclear.
Gene expression analysis of RNA-Seq data from human brains with PLCG2 variants identified inflammation-related pathways. In primary microglia, the uptake capacity of fluorescently labeled amyloid-beta peptide was found to be affected by the variants. To systematically investigate the impact of PLCG2 variants in AD, we generated mice with
PLCG2 variants and crossed them with 5xFAD amyloidogenic mice.
Our results demonstrated that M28L risk variant disrupted protein interactions between PLCG2 and upstream signaling proteins, impaired microglial response to plaques, suppressed cytokine release, downregulated disease-associated microglial
genes, and increased plaque deposition. Conversely, protective P522R variant with increased enzyme activity altered microglial activation state, promoted microglial response to plaques with altered cytokine levels, decreased plaque deposition, and ameliorated the impairment of synaptic plasticity and Y-maze alternation. Collectively, our study provides evidence that M28L variant had accelerated and exacerbated disease-related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression.
Overall, our findings identify a new AD risk variant in PLCG2 and demonstrate that PLCG2 variant confer specific microglial phenotypes and molecular signatures, providing a novel therapeutic target for delaying amyloid plaque-induced AD
pathologies.