MSC CM Potential for Alzheimer’s Disease Treatment

Alzheimer’s disease is a neurological degenerative disorder and the eighth leading cause of death in the United States. It affects approximately 6.2 million people, with annual healthcare costs amounting to around $305 billion [1]. The disease is characterized by abnormal protein synthesis, leading to neuroinflammation and damage to nerve cells. This results in hindrances to memory, cognition, and behavior due to the depletion of nerve cells and synaptic dysfunction [2].

Alzheimer’s Disease and Traditional Treatment Approaches

Currently, several drugs approved by the FDA for Alzheimer’s treatment include cholinesterase inhibitors (such as donepezil, rivastigmine, and galantamine) and memantine [3]. Patients using these drugs show mild cognitive function improvement in the first three months, but after 3-9 months, the drugs’ cognitive inhibitory ability gradually declines. The complexity of the disease’s pathogenesis and its unclear mechanisms contribute primarily to the inability of these drugs to cure the condition. Importantly, these treatments lack the ability to stimulate the regeneration of damaged nerve cells. Additionally, as the disease progresses, decreased cellular activity inhibits drug molecule transportation [4].

Therefore, drug-based treatments face limitations in effectiveness and precision. However, in recent years, mesenchymal stem cell (MSC) therapy has shown promising advancements in treating Alzheimer’s by enhancing functional recovery and regenerating damaged nerve cells [5].

MSC-CM Therapy in Alzheimer’s Treatment

Mesenchymal stem cells (MSCs) are the most extensively researched stem cells in Alzheimer’s treatment. MSCs function by secreting growth factors, anti-inflammatory proteins, membrane receptors, and microRNAs in conditioned media (CM). These elements limit nerve cell loss by preventing programmed cell death and stimulating the proliferation of nerve cells, synapse formation, and vascularization [6]. Furthermore, nerve growth factors (BDNF) and nerve-protecting factors like the oxidative enzyme superoxide dismutase 3 (SOD3) found in MSC-conditioned media (MSC-CM) help protect nerve cells from reactive oxygen species (ROS), reducing excessive superoxide accumulation and enhancing nerve cell survival [7, 8].

Extracellular vesicles (EVs) exert the neuroprotective effect of MSC-CM by providing antioxidant catalase and factors derived from other MSCs, such as cytokines, proteins, miRNA, and even healthy organelles that aid in nerve protection and restoration [Figure 1] [9]. Amyloid-beta (Aβ), observed in the brains of Alzheimer’s patients, decreases when MSC-CM is applied in experiments, reducing the expression caused by oligomers in both mice and ARPE-19 cells. To explore the potential role of peptides secreted from MSCs, researchers compared the peptidomics profile of MSC-CM. Subsequent biological analyses revealed that 3-8 out of 155–163 proteins in MSC-CM could be linked to SIRT1/pAKT/pGSK3β/β-catenin, tightly associated proteins in the self-destructive pathway. Particularly, insights into MSC-CM could be beneficial for Alzheimer’s prevention and treatment by reducing Aβ levels.

A preclinical study in mice with spinal cord injury has shown that miRNA-21 originating from MSC-secreted exosomes can inhibit programmed cell death in nerve cells by reducing the expression of PTEN and PDCD4 [10]. In another study, overexpression of miR-29b in exosomes released from MSCs reduced nerve cell death in a mouse model of Alzheimer’s disease, demonstrating improvements in memory and learning abilities [11]. Zaldivar and colleagues (2019) also showed promising results by injecting MSC-exosomes into Alzheimer’s disease-afflicted mice [12]. They demonstrated that exosomes present in MSC-CM stimulated the formation of nerve cells in the brain’s hemisphere, increased nervous system flexibility, and improved cognitive decline. These preclinical research findings indicate that MSC-CM provides a promising cell-free therapy for Alzheimer’s disease.

Figure 1: Effects of MSC-CM on nerve cells. MSC-CM contains biologically active molecules and nutritional factors such as VEGF-FGF-HGF-EGF with the ability to inhibit programmed cell death, reduce neural degeneration, increase the number of nerve cells and blood vessel formation, promote spinal cord recovery, increase ATP-NADH levels, and activate various signaling pathways at the neural cell level, such as AKT phosphorylation, JAK/STAT3 pathways [13].

Using MSC-CM in Alzheimer’s treatment offers several advantages over MSCs as it does not provoke strong immune responses or pose the risk of tumor development, ensuring patient safety. Preclinical studies using MSC-CM in Alzheimer’s disease-afflicted mice have generally shown positive results, yet human clinical trials are still lacking. Therefore, further in-depth research into the mechanism and additional human clinical trials in the future is essential to potentially replace traditional therapies, significantly improving Alzheimer’s disease condition, as well as other neurodegenerative diseases.

References

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