MicroRNA cargo in neuron‐derived small extracellular vesicles as a novel peripheral biomarker of brain insulin resistance and related cognitive impairment in patients with type 2 diabetes

Abstract

AbstractBackgroundBrain insulin resistance (bIR) is a critical risk factor for Alzheimer’s disease (AD); however, its relationship with peripheral insulin resistance remains unknown without blood‐based biomarkers to assess bIR. Here, we isolated highly pure neuron‐derived small extracellular vesicles (NDE) from plasma and characterized them with a panel of miRNAs related to bIR and cognitive impairment.MethodPlasma samples were obtained from the Look AHEAD‐MIND study with 28 cognitively normal subjects (18 female and 10 male) and 28 subjects with probable dementia (11 female and 17 male). This study was designed to investigate the effect of sustained weight‐loss interventions on cognitive trajectories in overweight/obese type 2 diabetics (T2D). NDE were enriched from plasma sequentially using L1CAM and synaptophysin surface markers by immunoprecipitation. The expression of specific miRNAs related to bIR (miR16‐5p, miR98‐5p, miR138‐5p, miR139‐5p, miR185‐5p, and miR342‐3p) and cognitive impairment (let7a‐5p, miR9‐5p, miR15b‐5p, miR29a‐5p, miR106‐5p, miR107, miR125b‐5p, and miR210‐3p) were analyzed by RT‐qPCR and correlated with corresponding clinical measures (MMSE score, Aβ1‐40, and Aβ1‐42 expression).ResultThe expression of miR106‐5p, miR125b‐5p, and miR‐210‐3p, exhibited significant upregulation in NDE from probable dementia cases (p = 0.0128; p = 0.0011; p = 0.0030, respectively), interestingly, only males exhibited these results. Similarly, miR185‐5p, and miR342‐3p, associated with bIR, exhibited significant upregulation in NDE exclusively from male probable dementia cases (p<0.0001; p<0.0001, respectively). Furthermore, while miR‐16‐5p upregulation was exclusive to male probable dementia cases (p = 0.0070), miR‐138‐5p was the only investigated miRNA that exhibited downregulation and was unique to female probable dementia cases (p = 0.0063). Aβ40 expression positively correlated with miR‐185‐5p, miR‐125b‐5p, miR‐342‐3p, and miR‐210‐3p (p = 0.0331; p = 0.0188; p = 0.0001; p = 0.0052; respectively) and Aβ42 positively correlated with miR‐125b‐5p, miR‐342‐3p, and miR‐210‐3p (p = 0.0058; p = 0.0027; p = 0.0089; respectively). MMSE score was negatively correlated with miR‐185‐5p, miR‐342‐3p, and miR‐210‐3p (p<0.0001; p<0.0001; p = 0.0089; respectively). However, miR‐106b‐5p and miR‐125b‐5p were negatively correlated with MMSE score only in males (p = 0.0337; p = 0.0140; respectively). Conversely, only one miRNA, miR‐138‐5p, positively correlated with MMSE score and was exclusive to females (p = 0.0164).ConclusionThis is the first study demonstrating the sex‐specific expression of AD‐ and bIR‐associated miRNAs in NDE, supporting the link between glucose metabolism dysregulation and the risk for dementia.