With the increasing aging of the global population, the incidence rate and mortality rate of AD are increasing every year. The 2018 World Alzheimer's disease report indicates that the average world population has 1 people every 3 seconds, the average survival time is 5.9 years, and the need for long-term care, seriously affecting social development, is a global problem threatening the human health [1]. According to the latest statistics of the World Health Organization, about 50 million people suffered from dementia globally in 2018, and the total number is expected to reach 82 million in 2030. By 2050, the number will increase to 152 million. The first recorded AD patients appeared in the early 20th century since then research on the etiology of AD has never been slack in the medical field. Although many pathogeneses and related targets of AD have been found, such as "β-amyloid (Aβ) hypothesis", "tau protein hypothesis", etc., but the complex pathogenesis involving multiple systemdysfunction has not been fully revealed [15, 16].
Even today, traditional drug therapy, especially cholinesterase inhibitors, is considered the first-line treatment for AD; however, the currently available treatment can only improve symptoms in a certain period, but cannot change the course of the disease. Nowadays, researchers are using stem cells and preparations developed by stem cells for the treatment of various neurodegenerative diseases such as AD. Some of them have confirmed that stem cells have broad clinical application prospects for the treatment of AD. Owing to the progressive nature of AD, the key prerequisite for the success of stem cell therapy is to make clear the inclusion criteria of clinical patients to be treated. Due to the involvement of hippocampal circuits in the early stages of the disease, some scholars suggest this region be a potential therapeutic target. An effective treatment strategy is the synaptic neuron loss [3].
The most important step in the development of stem cell therapy is choosing the right cell source. Taking into account the access to cells, ethical relationship, immunogenicity, efficiency, cost-effectiveness and other issues, MSCs were selected in this study. Compared with other mesenchymal stem cells, although hUC-MSCs have great advantages, its poor targeting and homing are still areas to be improved. Therefore, a new strategy to improve its targeting and homing is very important.
Magnetic targeting is a method to improve the efficiency of cell transplantation. At present, reports show that magnetic targeting can enhance the concentration of treatment cells up to 1.5–30 times, and significantly improve the treatment effect [17]. There are two important factors in the method of repairing magnetic targeted guidance:
(i) Magnetic labeling of therapeutic cells to form magnetized cells.
(ii) Using a magnetic field to target and guide magnetized cells.
At present, the endocytosis of cells is used to transplant nano level magnetic materials into cells. The magnet-labeled NPs will directly affect cell survival and biological function. These NPs will follow the cells into the patient's body, which will also have a certain impact on the body. Fe3O4 is the only metal oxide approved by FDA to be used in the biomedical field. It has been widely used in nuclear magnetic resonance, targeted drug carrier, and tissue engineering. In this case, SPIONs have been approved to be safe in clinical applications. SPION, as one of the most widely used MRI drugs, has been widely used in the first-line clinical diagnosis [18, 19]. There have been a lot of reports on the synthesis of SPION shell nanoparticles, in which the shell is composed of inorganic (such as silica) or organic (such as polymer) materials. Due to its unique coating quality and function, polydopamine (PDA) shell structure has attracted much attention. PDA has excellent biocompatibility and biodegradability, and will not produce long-term toxicity during retention in vivo, which improves the stability and biocompatibility of SPION@PDA.
Stem cell therapy has attracted more attention in recent years. However, many researchers still dispute whether stem cells can break through the BBB and enter the brain smoothly. In our study, we use SPION wrapped with dopamine to process MSCs and clarify the effect of MSCs modified with NPs on AD mice. The experimental data show that the NPs can not only help MSCs to pass through the BBB smoothly, but also further enhance the targeting of MSCs to the focus. Moreover, the MSCs modified with NPs improved cognitive function and learning ability. It also changes the important proteins in the hippocampus, such as Aβ deposition, tau protein, and BDNF.
The Morris water mazetest results revealed that APP/PS1 mice exhibit cognitive dysfunction, and this impairment is significantly alleviated after the injection of hUC-MSCs. Moreover, obvious results are seen for hUC-MSCs modified by Fe3O4@FDA. The role of hUC-MSCs on Aβ pathology is examined to determine the mechanism of the amelioration of hUC-MSCs on AD. Our results show that by decreasing the generation of CTF fragment, hUC-MSCs modified by Fe3O4@FDA and hUC-MSCs could ameliorate the pathology of AD. That's consistent with other researchers [20]. It showed that stem cells can not only improve the memory behavior and learning ability of AD but can also regulate the generation of Aβ in the early and middle stages of AD (7 and 10 months). However, in the late stage of AD (more than 12 months old), it can only affect the memory and other functions of AD and has no effect on the generation of Aβ [21–23].
To further confirm whether hUC-MSCs have an effect on neuronal cell death, OA-treated SHSY5Y cells were further cocultured with hUC-MSCs in a transwell system. The effect of hUC-MSCs on OA-induced apoptosis was detected. The results showed that hUC-MSCs could inhibit OA-induced PARP cleavage, caspase activation. Furthermore, OA-induced CTFα generation, GFAP, BDNF connexin 43, synaptophysin, and change in Tau protein levels have been influenced by cocultured with hUC-MSCs. These data strongly suggest that treatment with hUC-MSCs can inhibit OA-induced neuronal cell death by improving AD-related proteins.
The protein level of APP, BDNF, SYN, and GFAP, which correlates closely with neurogenesis and synaptic Tau connectivity was examined. The results showed decreasing levels of APP, pro-BDNF, and SYN, increasing in APP/PS1 mice when compared to WT mice. However, these proteins increased or decreased significantly in the hippocampus of APP/PS1 mice after treatment with hUC-MSCs.
Decreasing levels of BDNF are correlated with AD-related cognitive impairment severity, suggesting that reduced BDNF may be an early cofactor involved in the AD development. Furthermore, evidence shows that the neurotrophic factor signaling pathways are also closely related to AD development. A decrease in expression levels of BDNF is reported in the process of AD, which also participates in AD-related cognitive impairment [24, 25].
The early and core clinical manifestation of AD is hypomnesia, while the early pathological damage of AD is caused by the damage of synaptic function and structure. A significant decrease in synaptic connections in the hippocampus is observed in the early stage of AD.
SYN, a membrane protein on synaptic vesicles, is closely related to the release of neurotransmitters, synaptic formation, and ion channels of synaptic vesicles. The content of SYN protein expression reflects the synaptic function [26]. Research shows that loss of SYN is related to the cognitive function of AD patients, and it is also prior to the decrease of acetylcholine transferase activity [27].
As per recent evidence, astrocytes play an important role in the activation of AD, and the characteristic protein of astrocytes is GFAP. Astrocytes transform into reactive astrocytes when the central nervous system is damaged, which results in volume hyperplasia and hypertrophy, increasing the level of GFAP [28, 29].
Thus, our data indicate that Fe3O4@PDA-coated hUC-MSCs increase BDNF, SYN, and GFAP, which improves cognitive function in APP/PS1 transgenic mice by promoting hippocampal neurogenesis and enhancing hippocampal synaptic plasticity. The treatment mechanism of Fe3O4@PDA-coated hUC-MSCs remains unclear but is effective than treatment with hUC-MSCs. In a further study, we will investigate the mechanism of hUC-MSCs on the activation of endogenous neurogenesis and the reconstruction of synaptic connectivity mediated by BDNF, SYN, and GFAP.
In summary, the results of this study show that Fe3O4@PDA-coated hUC-MSCs improve the cognitive function in APP/PS1 mice model that exhibits well-established Aβ deposition by promoting neurogenesis and synaptic plasticity, increasing protein levels of BDNF, SYN, and GFAP. This study also suggests that regulation of hUC-MSCs generates excess neuroprotective factors, which could provide a viable therapy to treat AD.