Citation: Aquino, R.; de Concini, V.; Dhenain, M.; Lam, S.; Gosset, D.; Baquedano, L.; Forero, M.G.; Menuet, A.; Baril, P.; Pichon, C. Intrahippoc- ampal Inoculation of Aβ 1–42 Peptide in Rat as a Model of Alzheimer Model of Alzheimer Disease Identified MicroRNA-146a-5p as Blood Marker with Anti-Inflam- matory Function in Astrocyte Cells. Cells 2023, 12, 694. https://doi.org/ 10.3390/cells12050694 Academic Editors: Y-h. Taguchi and Hsiuying Wang Received: 20 December 2022 Revised: 9 February 2023 Accepted: 13 February 2023 Published: 22 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Article Intrahippocampal Inoculation of Aβ 1–42 Peptide in Rat as a Model of Alzheimer Model of Alzheimer Disease Identified MicroRNA-146a-5p as Blood Marker with Anti-Inflammatory Function in Astrocyte Cells Ruth Aquino 1,2,3 , Vidian de Concini 4 , Marc Dhenain 5 , Suzanne Lam 5 , David Gosset 1 , Laura Baquedano 2 , Manuel G. Forero 6 , Arnaud Menuet 3,4 , Patrick Baril 1,3, * and Chantal Pichon 1,3,7, * 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 * Correspondence: patrick.baril@cnrs-orleans.fr (P.B.); chantal.pichon@cnrs.fr (C.P.); Tel.: +33-(23)-825-7632 (P.B.); +33-(23)-825-5595 (C.P.) 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: microRNAs; miRNA-146a-5p; Alzheimer’s disease; Aβ 1–42 peptide; biomarkers; diagnosis 1. Introduction Alzheimer’s disease (AD) is a complex and multifactorial pathology that affects mil- lions of people around the world [1]. The appearance of amyloid plaques and the formation of neurofibrillary tangles (NFTs) are two representative features of AD, responsible for the gradual deterioration of cognitive functions such as loss of memory, language, and thinking ability. Amyloid plaques are deposits of amyloid beta (Aβ) peptide that accumulate in the extracellular matrix between nerve cells [2]. The Aβ peptides arise from the cleavage of Cells 2023, 12, 694. https://doi.org/10.3390/cells12050694 https://www.mdpi.com/journal/cells