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- Title
Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer's Disease.
- Authors
Garcia, Gonçalo; Pinto, Sara; Ferreira, Sofia; Lopes, Daniela; Serrador, Maria João; Fernandes, Adelaide; Vaz, Ana Rita; Mendonça, Alexandre de; Edenhofer, Frank; Malm, Tarja; Koistinaho, Jari; Brites, Dora
- Abstract
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 PSEN1ΔE9 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-1α + TNF-α induced morphological alterations and increased S100B, inflammatory transcripts, sAPPβ, cytokine release and exosomal miR-21. PPARα, 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.
- Subjects
ALZHEIMER'S disease; PLURIPOTENT stem cells; EXOSOMES; NEUROGLIA; MILD cognitive impairment; PHENOTYPIC plasticity; ASTROCYTES; MICROGLIA
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 21, p3377
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11213377