Role of clonal somatic mutations in microglia activation and Alzheimer’s disease

Boston Children'S Hospital, Boston MA

Investigators

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Abstract

Project Summary/Abstract Alzheimer’s disease (AD) and other neurodegenerative diseases are characterized by age-related onset and progressive neuronal loss. Neuroinflammation, the activation of the brain's innate immune system, is known to be critically involved in the initiation and development of neurodegeneration. As the primary immune cells in the brain, activated microglia have been recently reported to promote neuronal death during AD pathogenesis, yet the mechanisms by which age and genetic risk interact remain largely unknown. Somatic mutations accumulate in various cell types during the development and aging process of the human body. Clonal expansion of certain cell populations, driven by somatic mutations in genes regulating cell proliferation, has long been associated with an increased risk of cancer with age, but has only recently been linked to a growing list of non-cancer neurological diseases. Notably, somatic BRAF mutation in the microglial lineage has been implicated in histiocytosis-associated neurodegenerative conditions. Our preliminary results from two AD cohorts and with two sequencing technologies consistently show an excess of clonal somatic mutations in AD brains, particularly in proliferation-related genes of microglia. This new study aims to examine if the accumulation of somatic mutations contributes to an age-related increase of AD risk by activating clonal expansion of microglia, which subsequently induces neuroinflammation and neuronal loss in AD brains. The first Aim of the study is to identify somatic mutations by re-analysis of the existing bulk and single-cell RNA-seq datasets from large AD cohorts, and compare the transcriptome-wide burden and distribution of somatic mutation between different brain regions of AD patients and age-matched controls. In the second Aim of the study, molecule-barcoded ultra-deep panel sequencing will be applied to screen for clonal somatic mutations more sensitively among genes that regulate cell cycle and proliferation in AD and control brains, which will enable us to explore frequently mutated genes or pathways that may drive the clonal expansion of carrier cells during AD pathogenesis. The third Aim of the study will focus on the mutant fraction and functional impact of potentially pathogenic somatic mutations across different cell types in AD brains, especially for microglia, by combining single-cell RNA-seq and PRDD-seq, a method we developed for parallel analysis of somatic mutation and cell-type information from the same single-cells. The results of our study will shed new light on the contribution of somatic mutation to increased AD risk, and highlight the clonal expansion of microglia triggered by somatic mutations in proliferation-related genes as a potential mechanism of AD pathogenesis.