Deletion of microRNA‐21 exacerbates multiple phenotypes associated with Alzheimer’s disease through the RECK and ADAM10 pathway in a mouse model of Aβ amyloidosis

Abstract

AbstractBackgroundmicroRNAs have emerged as a new class of therapeutic targets that regulate the expression of target genes by binding their 3’‐untranslated regions. Growing evidence suggests that dysregulation of microRNAs may contribute to the onset and/or progression of various diseases. However, the functional and therapeutic implications of microRNA dysregulation in Alzheimer’s disease (AD) remain largely unclear. To gain insight into the roles of microRNAs in AD pathogenesis, we recently performed unbiased microRNA profiling with entorhinal cortices of AD and age‐matched non‐demented subjects. We found that miRNA‐21 (miR‐21) expression was markedly increased in AD patients. In addition, miR‐21 levels were increased in oligomeric amyloid‐beta (Aβ)‐treated neurons, suggesting that miR‐21 induction is directly associated with Aβ pathology. Therefore, we investigated the pathogenic/therapeutic potential of miR‐21 in AD.MethodTo investigate the role of miR‐21 in amyloid pathology in vivo, we crossed APP/PS1 mice with mir‐21−/− mice to generate APP/PS1;mir‐21+/+, APP/PS1;mir‐21+/− and, APP/PS1;mir‐21−/− mice. We evaluated the changes in the pathological features of AD, such as Aβ levels, amyloid plaques, and gliosis in these mice. Moreover, to investigate the effects of miR‐21 deletion on spatial learning and memory functions, we performed the Morris Water Maze (MWM) and Contextual fear conditioning (CFC) tests.ResultDeletion of miR‐21 increased the levels of insoluble and soluble Aβ40 and Aβ42 levels, as well as increased Aβ‐positive and X‐34‐positive plaque deposition in the cortex and hippocampus. CD45‐positive, IBA1‐positive microgliosis, and GFAP‐positive astrogliosis were also increased in the brain of APP/PS1;mir‐21+/− and APP/PS1;mir‐21−/− mice compared to APP/PS1;mir‐21+/+ mice. Mechanistic studies identified RECK as a potential target gene of miR‐21. miR‐21 deficiency upregulated the RECK protein level, leading to the inhibition of ADAM10 activity. This finding was also corroborated by the decrease in the soluble APPα level. Furthermore, we demonstrated that miR‐21 deficiency decreased spatial learning and contextual memory in MWM and CFC tests, respectively in APP/PS1 mice.ConclusionTaken together, our results demonstrated that miR‐21 may regulate multiple AD‐associated pathologies. Therefore, modulation of miR‐21 may represent a novel potential therapeutic strategy for AD.