Loss of Y is associated with multi-omic changes in immune cells from Alzheimer’s disease patients

Abstract

Alzheimer's disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of Y (LOY) in leukocytes is more prevalent in AD patients. We studied DNA methylation, gene expression and other epigenetic changes in monocytes and granulocytes with and without LOY from male AD patients and controls. We show that multi-omics of leukocytes can define new genes and confirm multiple ones already implicated in AD and we strengthen the role of LOY in disease development. The LOY-associated differences in DNA methylation levels were predominantly observed in regulatory regions, and supported by expression analysis showing down-regulation of immune genes. The single-cell transcriptomics highlighted that the AD patient-specific immune activation dominates over LOY-specific activation. Our findings agree with the hypothesis that age-related dysfunction of immune cells contribute to AD and that LOY is reflected by higher-level epigenetic changes with an AD-specific pattern.

Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases

“…In conclusion, our study sets the direction for further research regarding a probable functional role of LOY in intensifying features related to the suppressive phenotype of Tregs in TME and, as a consequence, a possible influence on immunotherapy response in CRC patients 44 . The presence of LOY has previously been associated with a considerable dysregulation of autosomal gene expression in leukocytes, in particular responsible for the immune-surveillance functions of circulating cells 9 , 15 , 16 . Here, we extend these findings to TME of CRC patients and this aspect warrants further studies.…”

“…Moreover, LOY affects different lineages of hematopoietic cells with varying frequencies and it plays a role in transcriptional dysregulation of autosomal genes in a pleiotropic, cell type specific manner 9 . Furthermore, dysregulation of immune genes was pronounced in cells with LOY, particularly related to immune checkpoint (IC) genes 9 , 15 , 16 . Major risk factors for LOY include age, smoking and germline predisposition 7 , 8 , 17 , 18 .…”

“…Notably, LOY likely has an impact on susceptibility to cancer 6 , 7 , Alzheimer’s disease (AD) 17 , cardiovascular diseases 19 , and severity of COVID-19 13 . Previous studies suggested that LOY disrupts proper functions of the immune system, especially the immune-surveillance mechanisms in AD and cancer 9 , 16 . Moreover, patients with prostate cancer showed higher levels of LOY in granulocytes and CD4 + T lymphocytes, suggesting that these cells, when affected by LOY, might convey an increased risk of cancer, and this finding motivated the current study 9 .…”

“…Our meta-analysis of two single-cell RNA sequencing (scRNA-seq) datasets focused on the analysis of infiltrating leukocytes in TME. Since LOY causes dysregulation of immune genes 9 , 13 , 15 , 16 , we hypothesized that it may also affect expression level of markers in TILs related to the efficacy of immunotherapy treatment.…”

Loss of Y in regulatory T lymphocytes in the tumor micro-environment of primary colorectal cancers and liver metastases

“…Notably, LOY likely has an impact on susceptibility to cancer [6,7], Alzheimer's disease (AD) [17], cardiovascular diseases [19], and severity of COVID-19 [13]. Previous studies suggested that LOY disrupts proper functions of the immune system, especially the immune-surveillance mechanisms in Alzheimer's disease and cancer [9,16]. Moreover, patients with prostate cancer showed higher levels of LOY in granulocytes and CD4+ T lymphocytes, suggesting that these cells, when affected by LOY, might convey an increased risk of cancer, and this finding motivated the current study [9].…”