ABSTRACT
Background: Emerging diagnostic modalities suggest that miRNA profiles within extracellular vesicles (EVs) isolated from peripheral blood specimens may provide a non-invasive diagnostic alternative for dementia and neurodegenerative disorders. Given that EVs confer a protective environment against miRNA enzymatic degradation, the miRNAs enriched in the EV fraction of blood samples could serve as more stable and clinically relevant biomarkers compared to those obtained from serum. Objective: To compare miRNAs isolated from EVs versus serum in blood taken from Alzheimer's disease (AD) dementia patients and control cohorts. Methods: We compared 25 AD patients to 34 individuals who exhibited no cognitive impairments (NCI). Subjects were Singapore residents with Chinese heritage. miRNAs purified from serum versus blood-derived EVs were analyzed for associations with AD dementia and medial temporal atrophy detected by magnetic resonance imaging. Results: Compared to serum-miRNAs, we identified almost twice as many EV-miRNAs associated with AD dementia, and they also correlated more significantly with medial temporal atrophy, a neuroimaging marker of AD-brain pathology. We further developed combination panels of serum-miRNAs and EV-miRNAs with improved performance in identifying AD dementia. Dominant in both panels was miRNA-1290. Conclusions: This data indicates that miRNA profiling from EVs offers diagnostic superiority. This underscores the role of EVs as vectors harboring prognostic biomarkers for neurodegenerative disorders and suggests their potential in yielding novel biomarkers for AD diagnosis.
Subject(s)
Alzheimer Disease , Atrophy , Biomarkers , Extracellular Vesicles , MicroRNAs , Temporal Lobe , Humans , Alzheimer Disease/genetics , Alzheimer Disease/diagnosis , Alzheimer Disease/blood , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , MicroRNAs/blood , MicroRNAs/genetics , Male , Female , Aged , Biomarkers/blood , Temporal Lobe/pathology , Temporal Lobe/diagnostic imaging , Magnetic Resonance Imaging , Middle Aged , Aged, 80 and overABSTRACT
The analysis of neural circuits has been revolutionized by optogenetic methods. Light-gated chloride-conducting anion channelrhodopsins (ACRs)-recently emerged as powerful neuron inhibitors. For cells or sub-neuronal compartments with high intracellular chloride concentrations, however, a chloride conductance can have instead an activating effect. The recently discovered light-gated, potassium-conducting, kalium channelrhodopsins (KCRs) might serve as an alternative in these situations, with potentially broad application. As yet, KCRs have not been shown to confer potent inhibitory effects in small genetically tractable animals. Here, we evaluated the utility of KCRs to suppress behavior and inhibit neural activity in Drosophila, Caenorhabditis elegans, and zebrafish. In direct comparisons with ACR1, a KCR1 variant with enhanced plasma-membrane trafficking displayed comparable potency, but with improved properties that include reduced toxicity and superior efficacy in putative high-chloride cells. This comparative analysis of behavioral inhibition between chloride- and potassium-selective silencing tools establishes KCRs as next-generation optogenetic inhibitors for in vivo circuit analysis in behaving animals.
