Alzheimer’s disease (AD), the predominant cause of late-life dementia, has a multifactorial etiology. Since there are few therapeutic options for symptomatic AD, research is increasingly focused on the identification of pre-symptomatic biomarkers. Recently, evaluation of neuron-derived exosomal markers has emerged as a promising novel approach for determining neuronal dysfunction. We aimed to identify novel neuron-derived exosomal markers that signify a transition from normal aging to Mild Cognitive Impairment (MCI) and then to clinically established AD, a sequence we refer to as AD progression. By using a Tandem Mass Tag-based quantitative proteomic approach, we identified a total of 360 neuron-derived exosomal proteins. Subsequent fuzzy c-means clustering revealed two clusters of proteins displaying trends of gradually increasing/decreasing expression over the period of AD progression (normal to MCI to AD), both of which were mainly involved in immune response-associated pathways, proteins within these clusters were defined as bridge proteins. Several differentially expressed proteins (DEPs) were identified in the progression of AD. The intersections of bridge proteins and DEPs were defined as key proteins, including C7 (Complement component 7), FERMT3 (Fermitin Family Member 3), CAP1 (Adenylyl cyclase-associated protein 1), ENO1 (Enolase 1), and ZYX (Zyxin), among which the expression patterns of C7 and ZYX were almost consistent with the proteomic results. Collectively, we propose that C7 and ZYX might be two novel neuron-derived exosomal protein markers, expression of which might be used to evaluate cognitive decline before a clinical diagnosis of AD is warranted.

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