An enriched environment prevents cognitive impairment in an Alzheimer’s disease model by enhancing the secretion of exosomal microRNA-146a from the choroid plexus

Abstract

Alzheimer’s disease (AD) is characterized by the extensive deposition of amyloid-β plaques and neurofibrillary tangles. We previously found that preserved function of astrocytes is associated with cognitively normal subjects with AD pathology. Here we show that an enriched environment (EE) can prevent cognitive impairment in AD model mice by ameliorating astrocytic inflammation and increasing synaptic density in the subiculum area of the hippocampus. In AD model mice treated with an EE, increased levels of microRNA (miR)-146a and down-regulation of NF-κB were observed in the hippocampus. In addition, increased levels of interferon (IFN)-γ were seen in serum from mice exposed to an EE. In vitro , enhanced miR-146a expression was observed in exosomes derived from the choroid plexus (CP) after IFN-γ treatment. In further in vitro experiments, we transfected miR-146a into Aβ/lipopolysaccharide-induced inflammatory astrocytes and showed that miR-146a ameliorated astrocytic inflammation by down-regulating tumor necrosis factor receptor-associated factor 6 and NF-κB. The present study indicates that following an EE, exosomal miR-146a derived from the CP cells is a key factor in ameliorating astrocytic inflammation, leading to synaptogenesis and correction of cognitive impairment.

Mindfulness Intervention Improves Cognitive Function in Older Adults by Enhancing the Level of miRNA-29c in Neuron-Derived Exosomes

“…MiR-146a has an anti-in ammatory effect by suppressing the expression of NF-κB; however, miR-146a is increased in the brains of AD patients 56 . We previously reported that intracerebroventricular injection of mesenchymal stem cells improves cognitive impairment in AD model mice by transferring exosomal miR-146a into the CNS 17 . In the present study, we found no signi cant change in the expression of miR-146a in NDEs, suggesting that miR-146a may not be involved in the cognitive improvement by MBSR.…”

“…In AD model mice, voluntary physical exercise can improve cognitive impairment by suppressing the expression of miR-132 in the hippocampus 15 . We previously reported that an enriched environment (EE) can prevent cognitive impairment in AD and diabetes model animals by increasing the level of miR-146a in the brain and serum 16,17 . An EE is a housing condition that stimulates experiencedependent plasticity due to physical and social surroundings such as toys and mazes 18 .…”

Mindfulness intervention improves cognitive function in older adults by enhancing the level of miRNA-29c in neuron-derived extracellular vesicles

“…The study was carried out in compliance with the ARRIVE guidelines. AD model mice, 5xFAD mice, were bread according to a previous study 17 ; they carry five mutations, which are the K670 N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human amyloid beta precursor protein (APP) and the M146L and L286V mutations in human presenilin 1 (PS1) 37 . In brief, male 5xFAD mice (#034,848, The Jackson Laboratory, Bar Harbor, ME, USA) were crossed with wild-type C57BL/6J females (Sankyo Lab Service Corp., Tokyo, Japan).…”

“…The right hemisphere was frozen immediately in liquid nitrogen and stored at − 80 °C for PCR analysis. The extraction of miRNA and mRNA and the synthesis of cDNA and PCR were performed as described previously 17 . In brief, the extraction of total miRNA and mRNA from the frozen right hippocampus was performed using the mirVana miRNA isolation kit (Thermo Fisher Scientific).…”

“…In AD model mice, voluntary physical exercise can improve cognitive impairment by suppressing the expression of miR-132 in the hippocampus 15 . We previously reported that an enriched environment (EE) can prevent cognitive impairment in AD and diabetes model animals by increasing the level of miR-146a in the brain and serum 16 , 17 . An EE is a housing condition that stimulates experience-dependent plasticity due to physical and social surroundings such as toys and mazes 18 .…”