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

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 Aβ1–42 peptides infused in the hippocampus of adult rats to mimic events of the early onset of non-familial AD disorder. Aβ1–42 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 APPswe/PS1dE9 transgenic mouse model. Of note, miRNA-146a-5p was exclusively dysregulated in the Aβ-induced AD model. The treatment of primary astrocytes with Aβ1–42 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 Aβ1–42 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.

A new automatic method for tracking rats in the Morris water maze

“…Potential confounding variables were minimised by placing the cages at the same level, the order of the evaluations was always the same and they were always performed at the same time, between 09:00 and 13:00. Animal handling and experimental procedures were approved by the ethical guidelines of the Universidad Peruana Cayetano Heredia System (CIEA-102069) [ 8 ]. Rats were obtained from the bioterium of the Research and Development Laboratory, Universidad Peruana Cayetano Heredia, Lima, Peru.…”

“…They were kept under temperature (25 ± 2 °C) and humidity (60%) controlled conditions. The rats' behaviour was monitored daily by animal care staff to ensure that the animals were safe and healthy [ 8 ]. Factors considered in deciding whether to euthanise before the planned end of the experiment included weight loss; severe pain that could not be controlled; tumour growth; coughing, wheezing or severe nasal discharge; nervous signs such as tremors, convulsions and paresis; incapacitation and other behavioural signs of distress, but not adverse events were observed.…”

“…In each trial, the rat was removed from the cage and placed in the water maze at one of four randomly determined locations with its head facing the pool wall and the interval between tests was 5 min. In all experiments, the initial position of the rat in the maze was chosen pseudo-randomly by placing the rodent in any of the quadrants, so that by the end of every fourth session the animal had already started the run in all four quadrants in any order, while the position of the platform was always the same [ 8 ].…”

Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

“…In this study, NF- κ B was infused into the hippocampus of rats and it was found that the NF- κ B pathway was activated; miRNA-146a-5p was upregulated, leading to a downregulation of IRAK-1 expression and a doubling of astrocytes. After treatment with the NF- κ B inhibitor BMS-345541, the expression of miRNA-146a-5p in astrocytes was significantly reversed, and IRAK-1 could be rescued, indicating that miRNA-146a-5p may pass NF- κ B pathway negative feedback loop which exerts anti-inflammatory function [ 122 , 123 ]. Other studies have confirmed that miR-15b may directly target BACE1 and downregulate its expression by inhibiting NF- κ B activation, reducing the production and accumulation of A β , and reducing the secretion of inflammatory cytokines [ 124 ].…”

Impaired spatial working memory and reduced hippocampal neuronal density in a rat model of neurocysticercosis

“…On the other hand, the use of animal models has been reported to evaluate cognitive problems associated with different pathologies, such as Alzheimer’s disease, which have been widely studied using behavioral tests ( Aquino et al, 2023 ), and to a lesser extent neuroinfectious diseases caused by viruses ( Dittrich et al, 1989 ; Elmore et al, 2014 ), parasites ( Parvin et al, 2016 ) and bacteria ( Becerril-Villanueva et al, 2018 ), where they have also reported cognitive deterioration in addition to alterations in hippocampus, decreased learning, and short- and long-term memory loss ( Tolman and Gleitman, 1949 ; Arime and Akiyama, 2017 ). In the case of memory studies in NCC, these are scarce.…”