
알츠하이머병 환자의 일부에서 MAPK 경로를 활성화하는 병원성 돌연변이를 가진 미세아교세포 클론이 선별적으로 증가하며, 이는 신경염증 반응을 유발한다.


coremsg

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer’s Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

One-Sentence Summary: A subset of Alzheimer Disease patients carry mutant microglia somatic clones which promote neuro-inflammation.

### Competing Interest Statement

FG has been a paid consultant (no equity) to Third Rock Ventures from 2018 to 2020. Sequencing costs and analysis in this study were covered in part by a SRA between Third Rock venture and MSKCC. This work led to patents PCT/US2022/037893/WO2023004054A1 'Methods and compositions for the treatment of alzheimer's disease' by MSKCC and PCT/US2018/047964 'Kinase mutation-associated neurodegenerative disorders' by MSKCC.

알츠하이머병 환자의 미세아교세포 클론성 염증 장애