Emerging Role of miR-21-5p in Neuron-Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder associated with neuron-glia dysfunction and dysregulated miRNAs. We previously reported upregulated miR-124/miR-21 in AD neurons and their exosomes. However, their glial distribution, phenotypic alterations and exosomal spread are scarcely documented. Here, we show glial cell activation and miR-21 overexpression in mouse organotypic hippocampal slices transplanted with SH-SY5Y cells expressing the human APP695 Swedish mutation. The upregulation of miR-21 only in the CSF from a small series of mild cognitive impairment (MCI) AD patients, but not in non-AD MCI individuals, supports its discriminatory potential. Microglia, neurons, and astrocytes differentiated from the same induced pluripotent stem cells from PSEN1 Delta E9 AD patients all showed miR-21 elevation. In AD neurons, miR-124/miR-21 overexpression was recapitulated in their exosomes. In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation. AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs. Their immunostimulation with C1q + IL-1 alpha + TNF-alpha induced morphological alterations and increased S100B, inflammatory transcripts, sAPP beta, cytokine release and exosomal miR-21. PPAR alpha, a target of miR-21, was found to be repressed in all models, except in neurons, likely due to concomitant miR-125b elevation. The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored.

Automated summary

MiR-21 is found to be overexpressed in glial cells and exosomes in Alzheimer's disease (AD), and also shows high expression in the cerebrospinal fluid (CSF) with potential discriminatory ability. MiR-21 elevation is observed in microglia, neurons, and astrocytes in AD patients, and may be associated with the repression of its target, PPAR alpha.