Stem Cell Therapy For Alzheimer’s Disease: An Overview Of Experimental Models And Reality Part 3

2.3.6  |  Novel balance theory

Stem cell therapy for AD is related to the integrative effect of different mechanisms, such as inflammation, immunoregulation, oxidative stress, apoptosis, autophagy, and angiogenesis (Figure 3).11 

The relationship between immune regulation and memory is a topic of great interest. Research shows that there is a close connection between the immune system and the memory system.

The immune system is a defensive force in our body that resists invasion and attack by pathogens. However, when the immune system breaks down, it can lead to the development of many diseases. There have been many studies proving that there is an important connection between the immune system and the memory system.

The immune system can maintain the body's health by playing a role in immune regulation. Immune regulation helps us fight disease while also promoting brain health. The brain is very sensitive to immune regulation, and when the immune system collapses, brain health is also affected. However, when we regulate our immune system to keep our body healthy, we also have a positive impact on our brain's memory.

The relationship between immune regulation and memory is mutually reinforcing. By actively regulating the immune system, we can reduce the occurrence of disease while also improving memory. On the other hand, when we improve our memory through things like exercising and maintaining a healthy diet, we also have a positive impact on our immune system. Therefore, we can say that the relationship between immune regulation and memory is interdependent.

In short, maintaining a healthy lifestyle and actively regulating the immune system in life are very important to promote the improvement of memory. We should always pay attention to our health and the status of our immune system, and keep ourselves healthy by exercising and maintaining a healthy diet. In this way, we can not only maintain the health of our body but also promote the health of our brain and improve our memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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These mechanisms alter the regional homeostasis in the hippocampus and mediate functional reconstruction by establishing a new balance.34 The new balance theory involves many advanced subjects, such as stem cell heterogeneity and therapeutic effect, the role of stem cell-derived extracellular vesicles or exosomes, and synaptic plasticity mediated by the crosstalk between T cells and microglia.

3  |  THERAPEUTIC EFFICIENCY OF STEM CELLS AND ITS INFLUENCING FACTORS

3.1  |  The evaluation of therapeutic effect

Stem cells such as NSCs, BM-MSCs, hUCB-MSCs, ESCs, and iPSCs have been investigated in different AD-like animal models. Furthermore, hUCB-MSCs, hPD-MSCs, hBM-MSCs, and hADSVF are being tested in different clinical trials. 

The evaluation of therapeutic efficacy involves (i) behavioral performance tests in animal models, and (ii) biochemical and pathohistological indicators. Examples of behavioral performance tests include Morris water maze, Barnes maze, Y-maze, T-maze, zero-maze, 8-arm maze, plusmaze discriminative avoidance task, shuttle box test, step down test, open field test, and dark avoidance.59,81 In clinical trials, the disease-related severity of all subjects is evaluated based on symptoms, cognitive function, memory, and quality of life. 

Biochemical and pathohistological changes of the AβPP/PS/tau triple transgenic model are informative in assessing co-evolving amyloid and tau pathologies, which are related to the pathomechanism of Alzheimer's disease.82 

The pathophysiological changes of Aβ and tau in the human brain occur before the onset of AD symptoms. There are high levels of Aβ42, t-tau, and p-tau in peripheral neurogenic exosomes and cerebrospinal fluid, which is powerful evidence for the diagnosis of AD.83,84.

3.2  |  Selection of animal models

Many animal models with Alzheimer's disease mimic the pathological characteristics of amyloidosis, such as the injection of Aβ proteins (e.g., Aβ1-42, Aβ1-40, Aβ25-35) and transgenic models.85–88 

The advantages of the injection method include a high success rate, good stability, rapidness, and the ability to use different animal species. However, this method inevitably causes mechanical damage to the cerebral tissue during the injection process, resulting in unpredictable injury. By employing genetic modification of APP, PS1, PS2, and APOE4, over-produced Aβ proteins are deposited in the brain to induce cognitive dysfunction. 

Of note, end-stage amyloid and tau pathologies in 3× transgenic AD mice are similar to those in sporadic AD, but the comprehensive investigation of AβPP, amyloid-β, and tau reveals key differences in biochemical and pathological characterization.82 Hyperphosphorylated tau is expressed along with AβPP/Aβ from an early age, whereas abundant extracellular amyloid plaques and paired helical filaments are observed at a late stage.82 

Transgenic models are useful in evaluating Aβ proteopathy, but not models of sporadic AD as they poorly mirror the pathogenesis of the human disease. In addition, AD-like animal models can also be established by other methods, such as intraperitoneal injection of d-galactose, direct injection of scopolamine to impair cholinergic neurons, gamma knife-mediated hippocampal damage, and so forth.89–92 

Interestingly, Aβ produced in the liver can induce neurodegeneration as well, which is another potential cause of Alzheimer's disease.93 Therefore, understanding the advantages and limitations of AD-like models will help select a suitable model that better approximates to human sporadic AD.82 Since very successful results in

animal models may reflect only limited aspects of human AD pathology, the track record of success in AD clinical trials is very poor.88,94.

3.3  |  To optimize stem cell types

Stem cell therapy can improve cognitive deficits as demonstrated by different AD-like animal models.11,42 So far, there are no conclusions regarding the comparison of therapeutic efficacy using different stem cells. Every cell type has its weaknesses or limitations. For instance, ESCs and hUCB-MSCs have ethical and immunogenic issues. Autologous NSCs from brain biopsy may face unacceptable attitudes and technical challenges. 

Relatively, BM-MSCs seem to have certain advantages, but they are still complicated by various problems, such as heterogeneity, low viability, and poor homing to lesion area. According to available data, the therapeutic efficiency of stem cells is altered due to (i) viability and heterogeneity, (ii) preconditioning, and (iii) gene manipulation. The passage number of cultured MSCs has a significant impact on the pluripotency. 

Mouse BM-MSCs can maintain functional morphology and multipotent state in the 4th generation.95,96 The expression of CD29, CD44, and CD90 on the membrane of rat BM-MSCs is gradually increased with passage numbers, reaching the peak after 5-6 generations.97,98 It is generally believed that the BM-MSCs before 7 passages have high viability and are suitable for stem cell therapy. 

The viability of MSCs may be enhanced through preconditioning, genetic modification, and a culture system. Stem cells preconditioned with dimethyloxalylglycine can enhance the therapeutic efficiency of Aβ-induced animal models.73 Other preconditioning methods, such as hypoxia, lipopolysaccharide (LPS), inflammatory cytokines, vitamin E, electromagnetic stimulation, and low-level lasers, can also improve the viability and immunomodulatory effect of stem cells.79,99 Mesenchymal stem cells can be modified through gene manipulation to enhance therapeutic efficiency. 

When BM-MSCs overexpressing VEGF are transplanted into APP/PS1 mice, the accumulation of amyloid deposits is reduced, which can significantly improve AD cognitive impairment in the middle and late stages of AD in mice.70 The transplantation of MSCs expressing antisnesemiR-937 lowers the deposition of Aβ proteins, stimulates the secretion of BDNF, and improves behavioral deficits as demonstrated by social recognition test and plus-maze discriminative avoidance task in APP/PS1 mice.74

3.4  |  To optimize delivery methods

As mentioned above, common methods for stem cell delivery include intravenous, intrahippocampal, intracerebroventricular, and intranasal. Each method has different advantages and weaknesses. Sometimes, the delivery method is a key factor in determining the therapeutic efficacy of transplanted stem cells. For example, it is necessary to repeatedly transplant stem cells to achieve a satisfactory result. 

It has been demonstrated that repeated transplantation is more effective than a single treatment regimen in the rat model.81,100 In the clinical trial NCT03117738, autologous adipose tissue-derived MSCs (AdMSCs) will be intravenously transfused 9 times at 2-week intervals. In clinical application, it is impractical for patients to receive multiple injections through the intrahippocampal or intracerebroventricular method.

4  |  PROSPECTIVE AND CHALLENGE

4.1  |  The biosafety of stem cells

The transplanted stem cells can alter their phenotype and function after being implanted in different tissues. Early study has discovered that the transplantation of ESCs can induce teratoma formation in vivo. 

Moreover, tumorigenesis has been reported from autologous important as its effectiveness. Interestingly, stem cell-derived exosomes (SC-Exos) act as cell-free mediators for the intercellular information exchange.29,76,101 The intracerebroventricular injection of SC-Exos can reduce Aβ plaques and tau tangles to improve cognitive function in transgenic APP/PS1 mice.101 The therapeutic advantages of stem cells and SC-Exos will be determined through parallel comparative studies in the future.

4.2  |  The standardization of stem cell culture

Whatever the tissue origin of stem cells, the specification of passage numbers represents an important parameter before being able to take advantage of stem cells with greater safety. So far, there is no standardized protocol for stem cell culture. For example, some studies have transplanted BM-MSCs at passages 1-2, but other studies have used BM-MSCs at passages 4-6 or passages 7-10.63,102 This may explain why therapeutic effects are so inconsistent. In addition to the type of stem cells, therapeutic efficiency is also affected by other factors, such as cell concentration, the species of recipients, and delivery methods. Thus, it is imperative to standardize the protocol for stem cell therapy.

4.3  |  Further evaluation of stem cell delivery

Common delivery methods in preclinical studies include stereotactic injection in the brain and intravenous injection in the peripheral vein. Stereotactic injection in the brain is a traumatic procedure, generally a single treatment. Its clinical application and therapeutic effect are thus limited. Multiple injections through peripheral veins can also improve the cognitive ability of AD-like models to a certain extent, but the optimization of this method needs further evaluation. Recently, nasal administration has been utilized to deliver stem cells, which can alleviate cognitive impairment in AD-like mice.58 However, this is a new alternative method whose effectiveness and stability have to be determined by future studies.

4.4  |  The prospects of stem cell therapy

Autologous stem cells are the most-used cell type owing to easy isolation and intravenous transplantation, without immunogenic and ethical issues.103 Still, some problems need to be resolved, such as long-term safety, optimum cell source, and delivery procedure, the response of donor cells to the AD-pathogenic microenvironment, and the mechanisms of action (Figure 3). Nevertheless, stem cells have been employed in the treatment of AD-like animal models for decades, and the accumulation of a large amount of research data has laid the foundation for the clinical trial of AD. Predictably, stem cell therapy will become a good candidate for the treatment of AD and other neurological diseases.

5  |  SUMMARY

Stem cell therapy for AD carries enormous promise, but it remains under development. Now, preclinical studies demonstrate proof of concept and reveal the underlying therapeutic mechanisms. Stem cell therapy has been tested in clinical trials. The accumulation of research data has laid the foundation for the future clinical treatment of AD patients. Perhaps the synergy of different methods can be employed in therapeutic strategy that involves cell modification, gene manipulation, and pharmacological intervention. Regarding the efficacy of stem cell therapy in AD patients, more time will be needed to conclude.

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China Grant (81941012), the CAMS initiative for Innovative Medicine of China (2021-I2 M-1-034), and the National Key Research and Development Project (2017YFA0105200).

CONFLICT OF INTEREST

The authors of this review are editorial board members of AMEM but were excluded from the peer-review process and all editorial decisions related to the publication of this article.

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