RESUMO
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.
Assuntos
Doença de Alzheimer , Atrofia , Biomarcadores , Vesículas Extracelulares , MicroRNAs , Lobo Temporal , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/sangue , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , MicroRNAs/sangue , MicroRNAs/genética , Masculino , Feminino , Idoso , Biomarcadores/sangue , Lobo Temporal/patologia , Lobo Temporal/diagnóstico por imagem , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
The neural cell adhesion molecule L1 (L1CAM) promotes neurite outgrowth via mechanisms that are not completely understood, but are known to involve the cytoskeleton. Here, we show that L1 binds directly to the microtubule associated protein 2c (MAP2c). This isoform of MAP2 is predominantly expressed in developing neurons. We found that the mRNA and protein levels of MAP2c, but not of MAP2a/b, are reduced in brains of young adult L1-deficient transgenic mice. We show via ELISA, that MAP2c, but not MAP2a/b, binds directly to the intracellular domain of L1. Remarkably, all these MAP2 isoforms co-immunoprecipitate with L1, suggesting that MAP2a/b associates with L1 via intermediate binding partners. The expression levels of MAP2a/b/c correlate with those of L1 in different brain regions of early postnatal mice, while expression levels of heat shock cognate protein 70 (Hsc70) or actin do not. L1 enhances the expression of MAP2a/b/c in cultured hippocampal neurons depending on activation of the mitogen-activated protein kinase (MAPK) pathway. Deficiency in both L1 and MAP2a/b/c expression results in reduced neurite outgrowth in vitro. We propose that the L1-triggered increase in MAP2a/b/c expression is required to promote neurite outgrowth.