Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer’s disease model by increasing the expression of microRNA-146a in hippocampus

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. Hallmarks of Alzheimer's disease (AD), the most common type of dementia, are amyloid-β (Aβ) plaques and tau tangles 1,2. However, several trials of drugs targeting Aβ including β-secretase inhibitors failed to slow cognitive decline, even though Aβ plaque formation was reduced 3. On the other hand, some post-mortem studies showed the existence of cognitively intact individuals with definite pathological features of AD 4. In addition, we revealed that astrocytic function is associated with the maintenance of cognitive function and that a beneficial type of astrocytes protects neuronal activity from the toxicity of Aβ and tau 5. Stem cell therapy has emerged as a novel treatment for many diseases. Bone marrow (BM)-or adipose-derived mesenchymal stem cells (MSCs) have been proposed to reduce the level of Aβ by activating microglia 6,7. Currently, clinical trials using autologous or allogeneic MSCs for AD are ongoing throughout the world 8. However, how MSCs repair the damaged astrocytes in AD models has not been investigated in detail. In a previous study, we reported that BM-MSC administration ameliorates diabetes-induced cognitive impairment 9. Hyperglycemia induces damage to astrocytes by increasing oxidative stress 10. BM-MSC-derived exosomes are taken up into astrocytes and can repair diabetes-induced astroglial damage by ameliorating mitochondrial abnormalities 9. In addition, we previously showed that microRNA (miR)-146a, which is contained in

Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders

“…In line with these findings are results obtained by Nakano and colleagues, who emphasized the important role of MSC-sourced miRNA-146 for MSC-Exo-dependent suppression of microglia and neuroinflammation in AD mice [ 30 ]. MiRNA-146 is a small, noncoding RNA molecule, which regulates inflammatory properties of microglia [ 30 ].…”

“…In line with these findings are results obtained by Nakano and colleagues, who emphasized the important role of MSC-sourced miRNA-146 for MSC-Exo-dependent suppression of microglia and neuroinflammation in AD mice [ 30 ]. MiRNA-146 is a small, noncoding RNA molecule, which regulates inflammatory properties of microglia [ 30 ]. MSC-Exos, in miRna-146-dependent manner, inhibited TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1) in microglia, resulting in the down-regulated phosphorylation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) [ 30 ].…”

“…Microglia-driven neuroinflammation aggravates the accumulation of Aβ proteins and importantly contributes to the development and progression of AD [ 3 ]. Accordingly, several studies demonstrated that MSC-Exos attenuated cognitive dysfunction of APP/PS1 mice by suppressing pro-inflammatory properties of microglia [ 29 , 30 , 31 ]. Ding and colleagues showed that umbilical cord (UC)-derived MSC-Exos (UC-MSC-Exos) modulated phenotype and function of microglia, attenuated neuroinflammation, and repaired cognitive dysfunction in APP/PS1 mice [ 29 ].…”

BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

“…Recently, extracellular vesicles (EVs), such as exosomes and microvesicles, have been attracting a strong research interest for use as natural drug delivery systems ( Chen et al, 2018 ; Tang and Wang, 2020 ). Mesenchymal stem cell (MSC)-derived exosomes have been reported to be involved in multiple physiology and pathology activities including osteogenesis, bone regeneration, osteoarthritis, cardiomyoblast hypoxia–reperfusion, cognitive impairment, inflammation, stroke, sepsis, and tumorigenesis ( Zheng et al, 2018 ; Huang et al, 2020 ; Jin et al, 2020 ; Nakano et al, 2020 ; Tan et al, 2020 ; Venkat et al, 2020 ; Xu et al, 2020 ; Zou et al, 2020 ). Jia et al (2020) report that exosomes secreted by young MSCs promote osteogenesis and bone formation in older rats.…”

Stem Cell-Derived Exosomes as Therapeutic Approach for Neurodegenerative Disorders: From Biology to Biotechnology

“…Similar results were also reported by Elia et al [ 150 ], who demonstrated that an intracerebral injection of extracellular vesicles from MSC exerts reduced Aβ plaque burden in early stages of a preclinical model of Alzheimer’s disease. The benefits of exosomal therapy were also reported by Nakano et al [ 151 ], who recently showed that the treatment of AD mouse model with BM-MSC-derived exosomes increased the expression of microRNA-146a in the hippocampus, decreasing the levels of nuclear factor kappa B (NF-κB) in astrocytes, leading to synaptogenesis and the correction of cognitive impairment. Furthermore, MSC-derived exosomes are also shown to suppress the inducible nitric oxide synthase (iNOS) in cultured primary neurons and ameliorate the neural impairment of CA1 synaptic transmission in an AD mouse model [ 152 ].…”