A review of stem cell therapy: An emerging treatment for dementia in Alzheimer's and Parkinson's disease

Abstract Aim This article aims to study the benefits and disadvantages of stem cell therapy, especially for patients who have dementia. Methods The databases PubMed, Google Scholar, and the National Library of Medicine were searched for literature. All papers on Alzheimer's disease, Lewy body dementia, Parkinson's disease, stem cell therapy, and its effect on dementia treatment were considered. Results Stem cell treatment has demonstrated promising outcomes in animal studies by positively modifying the degenerative alterations in dementia. However, it is not without drawbacks, such as ethical concerns while using embryonic stem cells and the danger of developing cancer if the cells undergo uncontrolled differentiation. Conclusion Although stem cell therapy has its risks, it has the potential to be a viable therapeutic option for patients with dementia if developed appropriately. Hence, more research and clinical trials are needed to establish its efficacy in this context.


INTRODUCTION
Dementia may be marked by disorientation, behavioral changes, and cognitive disturbances and is currently said to have affected around 50 million people around the globe, and it is predicted that by 2050, the number will increase to 132 million (Biehl & Russell, 2009). Dementia adversely affects the social and occupational life of patients (Duncan & Valenzuela, 2017). Alzheimer's disease (AD) and Parkinson's disease (PD) are two examples of neurological conditions that present with dementia. It is estimated that 5.8 million Americans have Alzheimer's disease, the most common cause of dementia (Duncan & Valenzuela,

Study selection
The inclusion and exclusion criteria were independently implemented by three authors (AUP, OU, and HO).

Difference of opinion
There was no difference of opinion among the authors.

CLASSES OF STEM CELLS
According to their origin, stem cells are categorized as either adult (somatic) cells or embryonic stem cells (Arvanitakis et al., 2019).
Embryonic stem cells are procured from blastocysts and can differentiate into any cell type. Adult stem cells, often referred to as somatic stem cells, are derived from adult tissues, most often bone marrow, and have a limited potential for regeneration .
Controversy about these terms is that adult stem cells, even if completely differentiated, can be converted to their embryonic form using recently found research techniques. In addition, adult stem cells can also be present in fetal tissue, the placenta, and umbilical cord blood.
As a result, a more accurate categorization is created based on stem cell potency (Arvanitakis et al., 2019).

THERAPEUTIC APPLICATION OF STEM CELLS
Because of their potential to multiply and give rise to multiple cell types, stem cells are an intriguing prospect for repairing damaged tissues. Stem cell therapy is increasingly being researched as a treatment option in neurocognitive disorders presenting with dementia, such as AD and PD.
Majority of the available research at present focuses on mesenchymal stem cells (MSC), which are pluripotent and aid in neurogenesis and angiogenesis. They also prevent the loss of neurons by exerting anti-apoptotic effects. This is brought about by releasing growth factors, neurotrophins, and cytokines. Thus, they aid in remyelination and regeneration. Additionally, they also interact with several immune cells, thus giving rise to anti-inflammatory effects (Lee et al., 2010). There

Stem cell therapy in Alzheimer's disease
Processes involved in the pathogenesis of AD include proliferation, apoptosis, angiogenesis, inflammation, immunomodulation and so on.
It is proposed that stem cell transplantation may alter these processes, thus repairing the neurological dysfunction and bringing about improvement in neurobehavioral function (Lees & Smith, 1983).

Removal of Aβ plaques
Research on animal models of Alzheimer's disease has proposed that Aβ-peptides may trigger apoptosis of neurons via oxidative stress (Goldberg et al., 2015, Oh et al., 2016. In addition, some studies suggest that transplanted stem cells may stimulate enzymes such as neprilysin-degrading enzyme, insulin-degrading enzyme, and endothelin converting enzymes, which have Aβ-degrading characteristics. Stem cells thus contribute to the reduction of hippocampal Aβ plaques (Harach et al., 2017, Oh et al., 2016.

Immunomodulatory actions
BMMSCs were able to speed up the activation of microglia, which participate in the removal of Aβ deposits in the brains of AD patients (Okazaki et al., 2008). This finding was suggestive of the fact that BMM-SCs are also capable of demonstrating immunomodulatory actions (Okazaki et al., 2008, Oh et al., 2016.

Anti-inflammatory effects
Furthermore, IL-10 signaling, although having anti-inflammatory actions, was found to be extremely high in AD patients. The levels of IL-10 were found to decrease after human stem cell transplantation (hMSC), which led to the hypothesis that blocking IL-10 could be therapeutically relevant in AD. Likewise, TNFα, which is involved in chronic inflammatory processes and cancer, was also decreased following hMSC transplantation (Safar et al., 2016).

Neurogenesis
Intravenously infused BMMSCs were able to migrate and reach the brain at the site of injury (Oh et al., 2016), where they differentiated into neuron-like cells and partially expressed choline acetyltransferase (ChAT) (Lees & Smith, 1983). The expression of ChAT is significant as it could be a potential mechanism of neurogenesis following transplantation of BMMSCs (Yang et al., 2004).
Moreover, expression of growth factor, chemokine, and extracellular matrix receptors on MSC surface could lead to production and upregulation of factors such as NGF, FGF-2, insulin like growth factor 1 (IGF-1), and BDNF, in turn facilitating endogenous regeneration and recovery of neurological function (Oh et al., 2016).

Angiogenesis
The presence of Aβ reduces the amount of soluble VEGF in the brain by binding to it and forming aggregates which ultimately lead to the loss of angiogenesis . hMSCs increased the expression of VEGF and vascular endothelial growth factor receptor-2 (VEGFR2) in ischemic areas of the brain (Qin et al., 2020, Nagaya et al., 2004, and increased the formation of peripheral vascular layers by differentiating into mural cells ).

Stem cell therapy in Parkinson's disease
The presence of α-synuclein is associated with cognitive impairment in Parkinson's disease dementia (PDD) (Kern et al., 2006). Although some studies have shown that transplantation of dopaminergic precursors caused improvement in motor symptoms of PD (Chen et al., 2004), studies evaluating the potential of stem cell transplantation in treating cognitive dysfunction in PDD are very few (Kern et al., 2006).
α-synuclein aggregates are known to be toxic to cells, leading to neuronal deaths in many α-synucleinopathies (Hirschi et al., 2003).
Neuronal cells release α-synuclein aggregates by the process of exocytosis (Hirschi et al., 2003), which are then taken up via endocytosis by neurons and glial cells (Van den Bos et al., 2022, Salem et al., 2014, Mo et al., 2012. Furthermore, it is suggested that the interaction between α-synuclein and N-methyl-D-aspartate (NMDA) receptors could facilitate clathrin-mediated endocytosis of NMDA receptors (Gomperts, 2016).
Clathrin and early endosome antigen 1 (EEA1) expression was found to be increased in cells treated with α-synuclein. This expression, however, was significantly decreased when cells were cocultured with MSCs. The internalization of α-synuclein via clathrin-mediated endocytosis was also inhibited by transplanted mesenchymal stem cells. This was observed to occur by altering the interaction between α-synuclein and NMDA receptors, thus reducing α-synuclein transmission and cell death induced by it (Hirschi et al., 2003).

OBSTACLES ENCOUNTERED IN STEM CELL THERAPY
Even though stem cell therapy has its advantages, establishing stem cell lines is a complicated process.