Protective Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells Against AD-Like Behaviors in Mice: Involvement with Regulating Glial Activation and its Associated Neuroinflammation and BDNF-Related Neuropathological Changes in the Hippocampus

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive ability. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can execute the function of bone marrow mesenchymal stem cells (BMSCs). Given the versatile therapeutic potential of BMSC and BMSC-exos, especially the neuroprotective effect, the aim of this study is to investigate the potential effect of BMSC-exos on the AD-like behavioral dysfunction in mice and explore the possible molecular mechanism.Methods: BMSCs were isolated from the femur and tibia of adult C57BL/6 mice, purified and sorted via flow cytometry technology, and cultured in vitro. The BMSC-exos were extracted and identified via transmission electron microscopy, and Western Blot was used to detect exosomes labeled proteins. A sporadic AD mouse model was established by intracerebroventricular injection of streptozotocin (STZ). 6 weeks later, BMSC-exos were given via lateral ventricle injection or caudal vein injection lasting for five consecutive days, and the control mice were intracerebroventricular given equal volume of solvent. The behavioral performance were observed via the Open field test (OFT), elevated plus maze test (EPM), novel object recognition test (NOR), Y maze test (Y-maze), and tail suspension test (TST). The mRNA and protein expressions of IL-1β, IL-6, and TNF-α in the hippocampus were measured via quantitative polymerase chain reaction (QPCR) and Western Blot, respectively. Meanwhile, the protein expression of Aβ1-42, BACE, p-Tau (Ser396), Synaptotagmin-1, Synapsin-1, and brain-derived neurotrophic factor (BDNF) in the hippocampus was detected using Western blot, and the expression of GFAP, IBA1, and DCX in the hippocampus was measured via immunofluorescence staining.Results: Lateral ventricle administration, but not caudal vein injection of BMSC-exos could improve the AD-like behaviors in STZ-injected mice model, as indicated by the increased number of rearing, increased frequency to the central area, and increased duration and moving distance in the central area in the OFT, together with improved preference index of the novel object in the NOR. Moreover, the hyper-activation of microglia and astrocytes in the hippocampus of the model mice were inhibited after treatment with BMSC-exos via lateral ventricle administration, accompanied by the reduced expression of IL-1β, IL-6, TNF-α, Aβ1-42, and p-Tau, and upregulated protein expression of synapse-related proteins and BDNF. Furthermore, results of Pearson test showed that the preference index of the novel object in the NOR was positively correlated to the hippocampal expression of BDNF, but negatively correlated with the expression of GFAP, IBA1, and IL-1β. Apart from a positive correlation between the hippocampal expression of BDNF and Syt-1, BDNF abundance was found negatively correlated with the markers of glial activation and the expression of inflammatory cytokines, Aβ, and p-tau, which were characteristic neuropathological features of AD.Conclusions: Lateral ventricle administration, but not caudal vein injection of BMSC-exos can improve the AD-like behavioral performance in STZ-injected mice, the mechanism of which might be involved with regulating glial activation and its associated neuroinflammation and BDNF-related neuropathological changes in the hippocampus.