Intrahippocampal Inoculation of Aβ1-42 Peptide in Rat as a Model of Alzheimer's Disease Identified MicroRNA-146a-5p as Blood Marker with Anti-Inflammatory Function in Astrocyte Cells

Ruth Aquino; Vidian de Concini; Marc Dhenain; Suzanne Lam; David Gosset; Laura Baquedano; Manuel G Forero; Arnaud Menuet; Patrick Baril; Chantal Pichon

doi:10.3390/cells12050694

Intrahippocampal Inoculation of Aβ_1-42 Peptide in Rat as a Model of Alzheimer's Disease Identified MicroRNA-146a-5p as Blood Marker with Anti-Inflammatory Function in Astrocyte Cells

Cells. 2023 Feb 22;12(5):694. doi: 10.3390/cells12050694.

Authors

Ruth Aquino^{1

2

3}, Vidian de Concini⁴, Marc Dhenain⁵, Suzanne Lam⁵, David Gosset¹, Laura Baquedano², Manuel G Forero⁶, Arnaud Menuet^{3

4}, Patrick Baril^{1

3}, Chantal Pichon^{1

3

7}

Affiliations

¹ Centre de Biophysique Moléculaire, CNRS UPR 4301, Rue Charles Sadron CS 80054, CEDEX 02, 45071 Orléans, France.
² Faculty of Science and Philosophy, Universidad Peruana Cayetano Heredia, Lima 4314, Peru.
³ Faculty of Science and Techniques, University of Orléans, 45067 Orléans, France.
⁴ Experimental and Molecular Immunology and Neurogenetic, UMR7355 CNRS, 45071 Orléans, France.
⁵ CEA, CNRS, Laboratoire des Maladies Neurodégénératives, Université Paris-Saclay, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
⁶ Professional School of Systems Engineering, Faculty of Engineering, Architecture and Urban Planning, Universidad Señor de Sipán, Chiclayo 14000, Peru.
⁷ Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France.

Abstract

Circulating microRNAs (miRNAs) have aroused a lot of interest as reliable blood diagnostic biomarkers of Alzheimer's disease (AD). Here, we investigated the panel of expressed blood miRNAs in response to aggregated Aβ_1-42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aβ_1-42 peptides in the hippocampus led to cognitive impairments associated with an astrogliosis and downregulation of circulating miRNA-146a-5p, -29a-3p, -29c-3p, -125b-5p, and-191-5p. We established the kinetics of expression of selected miRNAs and found differences with those detected in the APP_swe/PS1_dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aβ-induced AD model. The treatment of primary astrocytes with Aβ_1-42 peptides led to miRNA-146a-5p upregulation though the activation of the NF-κB signaling pathway, which in turn downregulated IRAK-1 but not TRAF-6 expression. As a consequence, no induction of IL-1β, IL-6, or TNF-α was detected. Astrocytes treated with a miRNA-146-5p inhibitor rescued IRAK-1 and changed TRAF-6 steady-state levels that correlated with the induction of IL-6, IL-1β, and CXCL1 production, indicating that miRNA-146a-5p operates anti-inflammatory functions through a NF-κB pathway negative feedback loop. Overall, we report a panel of circulating miRNAs that correlated with Aβ_1-42 peptides' presence in the hippocampus and provide mechanistic insights into miRNA-146a-5p biological function in the development of the early stage of sporadic AD.

Keywords: Alzheimer’s disease; Aβ1–42 peptide; biomarkers; diagnosis; miRNA-146a-5p; microRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Animals
Anti-Inflammatory Agents / metabolism
Astrocytes / metabolism
Interleukin-6 / metabolism
Mice
MicroRNAs* / metabolism
NF-kappa B / metabolism
Rats

Substances

amyloid beta-protein (1-42)
Anti-Inflammatory Agents
Interleukin-6
MicroRNAs
NF-kappa B
MIRN146a microRNA, rat

Grants and funding

This research was funded by CNRS and the University of Orléans. R.A. received a fellowship from the Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica (CONCYTEC), Cayetano Heredia Peruvian University, and the University of Orléans, through the French-Peruvian PhD program in Life Sciences. This work was also supported by European funding in Région Centre-Val de Loire (FEDER No. EX016008 TARGET-EX).