Single cell transcriptomic heterogeneity between sporadic early and late‐onset of Alzheimer’s disease

Abstract

AbstractBackgroundRegulatory T‐cells (Tregs) are key modulators of immune responses, and may play a key role in the pathophysiology of various neurodegenerative disorders, including Alzheimer’s disease (AD). However, the impact of Tregs modulation of immune responses during disease progression is poorly understood and still controversial. Thus, the main objective of our ongoing study is to depict a high‐resolution transcriptomic landscape of blood immune cells during spontaneous disease progression, which will facilitate a better understanding of the protective and/or pathogenic immune responses at different stages of the disease1‐3.MethodIn 2019 a Multi‐partner consortium to expand dementia research in Latin America (ReDLat) was created. The Consortium aims to combine genomic, neuroimaging and behavioral (clinical, cognitive, socioeconomic status –SES‐) data to improve dementia characterization and identify novel inroads to treat neurodegeneration in diverse populations. ReDLat initiative supports a basic platform anchored in Argentina, Brazil, Colombia, Peru, Mexico, Chile and USA. allowing us to expand our research and combine genomic, neuroimaging and behavioral (clinical, cognitive, socioeconomic status) data to improve dementia characterization.To investigate changes in individual T cell subsets across progressive clinical conditions we included 4 healthy controls (CTLs), 4 early‐onset sporadic AD (EOAD), 4 late onset AD (LOAD) and 4 Parkinson disease patients (PD) from ReDLat. Peripheral blood mononuclear cells (PBMCs) were isolated and a 5' single‐cell transcriptome and immune repertoire sequencing was performed.ResultsWe identified transcriptionally distinct subpopulations, heterogeneity of the immune system, T cell repertoire diversity and antigen specificity among groups. Interestingly, CD4+CD25+Foxp3+ T‐regs gene expression heterogeneity was observed between sporadic EOAD and LOAD, mainly related to cytotoxicity and inflammation. Our next step is to perform multiple association studies incorporating imaging, sex, cognition and socio‐economics status (SES).ConclusionAlthough full analysis is still in progress, we identified significant changes in individual T‐cell subsets among individuals across the four proposed groups, providing a unique opportunity to identify new risk factors and therapeutics targets for AD.1‐ Fu J (2021) Front. Aging Neurosci.2‐ Cira Dansokho (2016). Brain.3‐Baek H (2016) Oncotarget.