Abstract
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and tau. We previously reported that administration of bone marrow mesenchymal stem cells (BM-MSCs) ameliorates diabetes-induced cognitive impairment by transferring exosomes derived from these cells into astrocytes. Here, we show that intracerebroventricularly injected BM-MSCs improve cognitive impairment in AD model mice by ameliorating astrocytic inflammation as well as synaptogenesis. Although AD model mice showed an increase in NF-κB in the hippocampus, BM-MSC-treated AD model mice did not show this increase but showed an increase in levels of microRNA (miR)-146a in the hippocampus. Intracerebroventricularly injected BM-MSCs were attached to the choroid plexus in the lateral ventricle, and thus, BM-MSCs may secrete exosomes into the cerebrospinal fluid. In vitro experiments showed that exosomal miR-146a secreted from BM-MSCs was taken up into astrocytes, and an increased level of miR-146a and a decreased level of NF-κB were observed in astrocytes. Astrocytes are key cells for the formation of synapses, and thus, restoration of astrocytic function may have led to synaptogenesis and correction of cognitive impairment. The present study indicates that exosomal transfer of miR-146a is involved in the correction of cognitive impairment in AD model mice.
Highlights
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and tau
We hypothesized that local injection may be more effective, and intracerebroventricular administration of 1 × 105 bone marrow mesenchymal stem cells (BM-mesenchymal stem cells (MSCs))/mouse was performed in 13-month-old APP/PS1 mice, two times at a 2-week interval (Fig. 1a)
The treatment with Bone marrow (BM)-MSCs did not change the Aβ-positive area or neuronal number in the subiculum area, improvement in other pathological conditions such as an increase in synaptic density, amelioration of inflammation in astrocytes, and a decrease in the ratio of M1/M2 activated microglia was observed in AD model mice treated with BM-MSCs
Summary
We previously reported that administration of bone marrow mesenchymal stem cells (BM-MSCs) ameliorates diabetes-induced cognitive impairment by transferring exosomes derived from these cells into astrocytes. We show that intracerebroventricularly injected BM-MSCs improve cognitive impairment in AD model mice by ameliorating astrocytic inflammation as well as synaptogenesis. The present study indicates that exosomal transfer of miR-146a is involved in the correction of cognitive impairment in AD model mice. Bone marrow (BM)- or adipose-derived mesenchymal stem cells (MSCs) have been proposed to reduce the level of Aβ by activating m icroglia[6,7]. We reported that BM-MSC administration ameliorates diabetes-induced cognitive impairment[9]. BM-MSC-derived exosomes are taken up into astrocytes and can repair diabetes-induced astroglial damage by ameliorating mitochondrial abnormalities[9]. Exosomes that are secreted from BM-MSCs, ameliorates diabetes-induced astroglial inflammation via transfer into astroglia. Exosomes that are secreted from BM-MSCs, ameliorates diabetes-induced astroglial inflammation via transfer into astroglia11. miR-146a is an anti-inflammatory microRNA that down-regulates NF-κB activity by repressing interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6)[11]
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