Deciphering the cell-intrinsic effect of DNMT3A clonal hematopoiesis in circulating monocytes: potential mechanistic insights into a protective role in Alzheimer's disease

BackgroundRecent evidence showed an unforeseen connection between clonal hematopoiesis (CH) and protection against Alzheimers disease (AD) and found mutant bone marrow-derived cells infiltrate the brain and acquire a microglial-like phenotype, correlating with reduced neuritic plaques and neurofibrillary tangles in non-AD individuals. CH, characterized by somatic mutations in hematopoietic stem cells leading to clonal expansion of immune cells, has previously been associated with the exacerbation of various age-related diseases. Methods and ResultsAs the mechanism behind this protective effect remains unclear, our study introduces a novel method, MutDetect-Seq, capable of discerning cell-intrinsic effects of CH mutations. Single-cell RNA sequencing profiles in patients with DNMT3A CH mutations were assessed, hypothesizing that mutant cells might augment phagocytosis, potentially mitigating neurodegenerative processes. Indeed, DNMT3A mutant monocytes exhibited a distinct pro-phagocytic gene signature as demonstrated via upregulation of prototypical phagocytotic genes like CALR, FCGR1A, CYBA, S100A8, S100A9 and FCER1G. Upregulation was validated in vitro with DNMT3A silenced THP1 macrophages. Furthermore, upregulated gene pathways in mutant monocytes associated with phagocytosis, suggesting bone marrow-derived monocytic cells with CH DNMT3A mutations could replenish the brains phagocytic capacity, counteracting age-related declines in microglial phagocytosis, and thereby causatively reducing neurodegenerative processes in AD. ConclusionThis study reveals critical phenotypic disparities between DNMT3A CH driver harboring mutant and wild-type monocytes, shedding light on a potential mechanism underlying the unexpected protective role of CH in AD progression and offering insights into the effects of different CH mutations in disease contexts.