Longitudinal microRNA profiling of neuronal-enriched exosomes associated with cognitive function and decline

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2024-03-21

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0000-0001-9429-1993 (Subasinghe, Kumudu)

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Abstract

Background. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that disproportionately affects several racial/ethnic groups, including Mexican Americans (MAs). Evidence suggests that early alterations in the AD brain can propagate to local and distal cells through small biological packages called exosomes. Exosomes secreted by neurons are capable of mediating cell-to-cell communication through their bioactive cargo, leading to metabolic and epigenetic reprogramming in target cells. Exosomes derived from neurons have been detected in plasma and isolated from other subpopulations using the neural cell adhesion molecule CD171. These neuronal-enriched exosomes (NEEs) cross the blood-brain barrier and thus represent an easily accessible derivative of otherwise inaccessible brain tissue in living humans. Small, non-coding RNAs called microRNAs (miRNA) are transcribed from nuclear DNA and function as strong intracellular expression regulators. miRNAs, which can be selectively packaged and transported by exosomes, have been shown to significantly alter the expression patterns of target cells. This project aims to identify the aberrant miRNA profiles that correlate with disease progression and key comorbidities (e.g., type 2 diabetes (T2D), hyperlipidemia, hypertension) in NEEs of plasma from MAs and Non-Hispanic Whites (NHWs). Hypothesis. We hypothesize that population-specific differences in NEE miRNA cargo will reflect cognitive function and decline. Methods. Longitudinal plasma samples (two time points, 2 years apart) received from the Texas Alzheimer’s Research and Care Consortium (TARCC) were processed using a two-step method that involves precipitation of total exosomes followed by NEE capture with a biotinylated antibody against the neuronal surface marker, CD171. After isolating RNA from NEEs, miRNAs were then profiled using next-generation sequencing. These profiles were then analyzed for differential miRNA expression in individuals with cognitive impairment compared to the normal control group. Results. Our preliminary quality control and sequencing data confirmed the successful isolation of miRNA from NEEs. We identified specific miRNA candidates that were differentially expressed in NEEs from cognitively impaired subjects compared to healthy controls. These miRNAs target gene networks that have been implicated in AD pathophysiology. Conclusion. This innovative workflow along with the unique sample type provides novel insight into the role of exosomal miRNA cargo in AD pathogenesis, identifying novel, population-specific targets for biomarker/diagnosis as well as therapeutic design. Further, this approach provides a conceptual framework for blood-based exosomal profiling in other complex diseases characterized by epigenetic dysregulation and systemic inflammation.

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Research Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Department of Microbiology, Immunology & Genetics (Genetics) Award - 1st Place

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