Biomarkers for Alzheimer’s disease and brain brain insulin resistance using plasma Extracellular vesicles:a systemtic review

Background and Objective:Current theories regarding the pathogenesis of Alzheimer’s disease(AD)implicate brain insulin resistance(IR)as a key factor. Extracellular vesicles (EVs)are secreted from nearly every cell type throughout the body .These small vesicles are thought to serve a variety of functions in both healthy and disease states, from cellular waste removal to shuttles of various proteins. One of the most exciting aspects of EV research is their potency to be used as sources for biomarkers for neurodegenerative diseases .The objective of this study is to provide an overview of biomarkers for AD and brain IR using plasma EVs enriched for neuronal origin. These biomarkers include pathogenic proteins (total tau and Amyloid beta(Aβ). Search Method:This study is a review article with the use of systematic search in valid databasessuch as Sciencedirect,EBSCO,Proquest and PubMed which were done in 2018 and 2019. Findings:There is a novel analysis demonstrating the close spatial correlation between brain expression of genes implicated in IR(using Allen Human Brain Atlas data)and tau and beta-amyloid pathologies.A bold hypotheses that baseline differences in the metabolic reliance on glycolysis is proposed,and the expression of glucose transporters(GLUT)and insulin signaling genes determine the vulnerability of different brain regions to Tau and/or(Aβ)pathology,and that IR is a critical link between these two pathologies that define AD.Secreted EVs have been shown to contain hyperphosphorylated tau as well as Aβ, the latter through sorting into multivesicular bodies(MVB’s).Moreover,astrocytic derived EV’s have been shown to mediate apoptosis leading to brain cell loss.Lastly,there is evidence to support that tau overexpression selectively recruits mitochondrial proteins implicated in neurodegeneration to exosomes,providing a novel link between tau exosome secretion and AD pathology.However, there are also findings that support a neuroprotective role of exosomes in the face of neurodegenerative diseases.Additionally,it is thought that EVs released by astrocytes may serve to regulate synaptic transmission,as well as synaptic regeneration following injury,supporting a neuroprotective role.Besides,findings establish the links between IR and AD, with the discovery of Insulin receptor substrate1(IRS-1)peptides in neural-origin plasma EVs introducing a unique biomarker for brain IR to provide hope for a blood-based diagnostic assay to diagnose AD preclinically. Conclusion: This review attempted to unravel the complex mechanisms underlying brain-specific IR and highlight links to the AD pathogenic cascade.

کلیدواژه ها:

Alzheimer’s disease ، insulin resistance ، exosomes ، IRS-1