Keywords

9.1 Introduction

In 1907, Alois Alzheimer first reported Alzheimer’s disease (AD) (Choi et al. 2014a, b). However, 60–80% of dementia cases are caused by AD, characterized by memory loss and cognitive disorder which affects the quality of life. AD is a progressive neurodegenerative disorder, where the symptom of dementia is gradually elevated over a number of years. In the early stages of the AD, mild memory loss occurs, but in the later stage, the patients lose the ability to converse and the ability to respond to their environment. AD severely affects the human health, as it is the sixth leading cause of mortality in the United States. The average life duration of Alzheimer’s patient is 8 years after the AD’s symptoms become noticeable, but survival range can vary from 4 to 20 years, depending on the age, lifestyle, diet, and health condition. In 2010, the estimated economic burden of AD’s treatment was $172 billion in the United States and $604 billion worldwide that will be tripled by 2050 (Wimo et al. 2010). In India, approximately 3.7 million people were suffering from AD, and this number is expected to double by the year 2030 (Alzheimer’s and Related Disorders Society of India (ARDSI) 2010).

Two types of AD are reported: (i) familial and (ii) sporadic. Familial AD is caused by an autosomal genetic mutation in the genes responsible for Aβ plaques. This genetic mutation is related to the amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2). However, familial AD is rare in prevalence and less than 5% of familial AD cases are reported (Selkoe 2001; Prasher et al. 1998; Rosen et al. 2010; Marchetti and Marie 2011; Genin et al. 2011). Sporadic AD is ubiquitous in nature and caused by the interaction between genetic profile and environmental factors (Duncan and Valenzuela 2017; Persson et al. 2014). The cardinal pathologic features of AD include the aggregation of two types of misfolded proteins (amyloid beta and tau) (Allen et al. 2011; Eckman and Eckman 2007). Amyloid beta (Aβ) protein is a pathological cleavage product of the APP. Aβ protein accumulates into plaques and minor oligomers. Mutations in APP genes or in APP processing pathway genes are linked to the inherited familial AD (Huang and Mucke 2012). Tau is a microtubule-associated protein that accumulates intracellularly as neurofibrillary tangles (NFTs) which is a pathological feature closely linked with cognitive decline in the AD. However, mutations in tau protein lead to cause frontotemporal dementia, not AD (Huang and Mucke 2012).

A rising accord inside the field is that treatment of AD patients with currently available medicines comes late, which is the result of vital neuronal cell loss within the brain. To combat these problems, human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC)/mesenchymal stem cell (MSC)-derived neural cells have been suggested as powerful replacement therapy for AD (Fig. 9.1). In this chapter, the current state of research in the etiology of AD, probable challenges, and techniques for using stem cell-based treatment will be discussed briefly. Recent studies that have developed promising cell types and clinical investigations that could be used to combat this detrimental disease in the future will also be highlighted.

Fig. 9.1
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Stem cell therapy in AD

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9.2 Pathophysiology of Alzheimer’s Disease

AD is distinguished by extracellular amyloid plaques and intracellular NFT features. Amyloid-β (Aβ) protein is the major constituent of plaques associated with AD (Fig. 9.2). The pathophysiology of AD involves several neurotransmitters system and processes (Lin et al. 2001). Three hallmarks of the AD are β-amyloid plaques, neurofibrillary tangles, and neuronal cell death.

Fig. 9.2
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Pathogenesis of AD represented by interacting damage pathways lead by soluble oligomers of the amyloid beta peptide

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Recently, recognized characteristics of AD include degeneration of synapses, aneuploidy, neuronal loss, granulovacuolar degeneration, and amyloid plaques. Three types of amyloid plaques are known in the brain of AD patients:

  1. 1.

    Diffuse plaques: contain no amyloid core

  2. 2.

    Neuritic plaques: consist of a central amyloid core surrounded by neurites

  3. 3.

    Burnt-out plaques: consist of an isolated amyloid core

Apart from the amyloid plaques and tangles, globular and non-fibrillar proteins are continuously released in the AD patient’s brain. Cellular changes include short-term and rapid degeneration of neurons which leads to neuronal death when Aβ proteins remain globular.

A few theories related to AD such as the cholinergic, Aβ, tau, and inflammation hypothesis have been explained. Some of them are listed below to understand the mechanism of this disorder:

  1. 1.

    Changes in brain structure: The characteristic of the AD on a macro level is the progressive loss of brain tissue. The cortex atrophies are responsible for memory formation in the brain.

  2. 2.

    Degenerative processes in AD: AD is characterized on a micro level by three neuropathologic hallmarks: extracellular β-amyloid plaques, intracellular NFTs, and neuronal degeneration. β-Amyloid plaques play an important role in AD pathogenesis which is known as “amyloid cascade” (Swerdlow 2007).

9.3 β-Amyloid Hypothesis

β-Amyloid plaques are aggregates of insoluble peptides formed after the cleavage of APP. Three enzymes, namely γ-secretase, β-secretase, and α-secretase, participate in the APP cleavage. However, APP cleavage by β-secretase followed by γ-secretase produces a soluble 40-amino acid peptide. In addition, γ-secretase cleaves APP that forms nonsoluble 42-amino acid peptide Aβ42 or Aβ which aggregates as β-amyloid plaques. There are three genes involved in the formation of Aβ: APP, PS1, and PS2. PS1 and PS2 genes code for presenilin which is a subunit of γ-secretase. Tau protein hyperphosphorylation occurs after plaque formation in the brain (Selkoe 2002). Neurofibrillary tangles (NFTs) result from damage of neuronal microtubules caused by tau protein modification (Imbimbo et al. 2005). Tau protein disrupts the collapse structure of microtubules and destroys the neuron’s transport and communication system. Modifications in tau lead to its oligomerization and NFT production (Maccioni et al. 2010).

9.4 Cholinergic Hypothesis

Loss of cholinergic neurons is one of the pathologies of AD. In that case, more than 75% of cholinergic neurons are reduced in AD patient’s brain (Perry et al. 1978). However, acetylcholine is involved in memory; thus, loss of cholinergic activity relates with impairment of memory. Acetylcholine attaches to the post-synaptic receptors: muscarinic and nicotinic. Pre-synaptic nicotinic receptors influence the release of acetylcholine, serotonin, norepinephrine, and glutamate which have a role in AD pathophysiology.

9.5 Glutamatergic Hypothesis

Glutamatergic neurons form the projections which influence the cognition in the brain. AD pathology is linked to only one type of receptor, that is, NMDA receptor which then undergoes low-level activation in AD patient’s brain. However, dysregulation of the glutamate NMDA receptor is responsible for neuronal damage which interferes with normal signal transduction (Danysz et al. 2000). It can lead to the production of APP which is related to plaque development and tau hyperphosphorylation.

9.6 Oxidative Stress Hypothesis

Aβ generates the reactive oxygen and nitrogen species which have an unpaired extra electron and also induces lipid peroxidation. The free radicals cause cellular and molecular damage in neuronal cells. The brain can be damaged from oxidative stress because of high oxygen utilization rate and antioxidant enzymes as compared with the other organs. Upregulation of cytokines and DNA damage in neurons have an essential role in AD progression.

9.7 Chronic Inflammation Hypothesis

β-Amyloid deposition in neurons and NFTs causes inflammation in response to cellular damage. Inflammation leads to the increased number of prostaglandins, produced by COX-1 and COX-2, localized in distinct areas of the brain. Inflammation occurs within or adjacent to the neuritic plaque. Antichymotrypsin, macroglobulin in neuritic plaques, and activated microglia codes for interleukin-1 and interleukin-6 also are detectable in case of the inflammation-related AD.

9.8 Cholesterol and Other Factors

Cholesterol is also implicated in AD pathogenesis. Elevated cholesterol levels raise Aβ production, and thus, the risk of AD progression increases (Reiss 2005). During the AD progression, brain regions become altered, and reduced serotonin levels play an important role in depression and anxiety which are common in an AD patient (Mössner et al. 2000; Lai et al. 2005).

9.9 Stem Cells Used in Alzheimer’s Treatment

Stem cells are undifferentiated cells that possess self-renewal and differentiation property. Self-renewal is described as the ability to undergo numerous cell cycle divisions, resulting in identical daughter cells, and differentiation capability is the development of specialized cells from the undifferentiated stem cells (Tabassum et al. 2017). On the virtue of origin, stem cells can be categorized into embryonic stem cells (ESCs) and adult stem cells, and based on potency, these cells are categorized into totipotent, multipotent, pluripotent, and unipotent. Due to the differentiation properties of stem cells into neuronal-like cells, they can be used for the treatment of Alzheimer’s disease. The human body generates four types of stem cells: neural stem cells (NSCs), MSCs, ESCs, and iPSCs. These cells have unique properties; thus, they are the most suitable candidates for stem cell therapy.

Embryonic Stem Cells (ESCs)

ESCs are pluripotent stem cells which are obtained from the inner cell mass of the blastocyst that gives rise to all cell types except placenta. Researchers successfully differentiated the ESCs into several specific neural cell types including dopaminergic neurons in vitro (Krencik et al. 2011; Malmersjo et al. 2009). The direct transplantation of ESCs showed high risks of teratoma formation due to their potent differentiation ability (Kooreman and Wu 2010). Moreover, various rodent studies demonstrated that the transplantation of ESC-derived NSCs shows no tumorigenesis, but to confirm these results, further research is needed (Araki et al. 2013; Tang et al. 2008). Along with tumorigenesis, rejection of transplanted ESC-derived tissues by the immune system occurred (Pearl et al. 2012).

Induced Pluripotent Stem Cells (iPSCs)

iPSCs are pluripotent stem cells which are reprogrammed from adult fibroblasts by using four transcription factors including Oct3/4, Sox2, Klf4, and c-Myc that are pretty much similar to the ESCs (Takahashi and Yamanaka 2006). These cells are reprogrammed into pluripotency state, having the capability to differentiate into different types of cells including neurons (Cooper et al. 2010) and neurospheres (Nori et al. 2011). Researchers used the iPSC-derived glia cells regarding the inflammatory response in Alzheimer’s disease (Holtman et al. 2015). In 2014, Takamatsu revealed that iPSC-derived macrophages express neprilysin and β-amyloid-degrading protease (Takamatsu et al. 2014). However, certain unsolved problems are still present regarding the clinical usage of iPSCs such as tumor formation, immunogenicity, long-time safety, genetic defects, and optimal reprogramming (Tolosa et al. 2016; Araki et al. 2013). Therefore, iPSC-based treatment for AD has been more focused on the establishment of cell-based disease models as compared to treatments (Choi et al. 2014a, b; Yagi et al. 2012; Sproul et al. 2014). Israel and coworkers highlighted the cholinergic neurons of the basal forebrain because of their dysfunction in the early stage of AD (Israel et al. 2012). We know that there is a widespread degeneration in the later stage of the AD, so the protocol using iPSCs should be more elaborated (Pen and Jensen 2017).

Neuronal Stem Cells (NSCs)

NSCs are found within the brain. In the past few decades, it was thought that the process of neurogenesis takes place in the fetus; however, the recent studies demonstrated that neurogenesis also occurs in an adult’s brain. NSCs were found in the sub-granular zone and sub-ventricular zone of the brain (Taupin 2006; Mu and Gage 2011). These cells are differentiated into neurons, astrocytes, and oligodendrocytes (Taupin 2006). Due to the differentiation capability, NSCs are considered as the best choice for the replacement of injured neurons. In 2001, for the first time, Qu and coworkers proved the replacement of injured neuron by implanting human NSCs into the mature rat’s brain (Qu et al. 2001). The results showed that NSCs survived and differentiated into neurons and astrocytes in rat’s brain. Moreover, memory impairment was also observed in mature rats after the transplantation when evaluated with the control (Qu et al. 2001). However, NSC isolation from the adult’s brain is complicated, so current studies mainly use fetal NSCs, which could also raise ethical problems. To combat these problems, researchers focused on the MSCs, and it was found that bone marrow MSCs (BM-MSCs), adipose tissue (AT-MSCs), and umbilical cord blood MSCs (UC-MSCs) could be trans-differentiated into neuronal cells (Brazelton et al. 2000; Mezey et al. 2000; Kim et al. 2012a, b).

Mesenchymal Stem Cells (MSCs)

MSC-based therapy has an advantage over other cell-based therapy because it can be given intravenously and has blood barrier penetration and low tumorigenicity (Oh et al. 2015; Ra et al. 2011). The in vitro transplantation of MSCs in AD cell model augmented the metabolic activity and survival which help to rescue the patients with AD. Co-culturing of human MSCs and mouse microglia cells increased the expression of neprilysin (Aβ-degrading enzyme) (Kim et al. 2012a, b). BM-MSCs show the immunomodulatory capability by releasing the soluble factors including TGF-β, IL-6, IL-10, and PGE2 (Ramasamy et al. 2007; Aggarwal and Pittenger 2005). These factors inhibit the functioning of monocyte-derived dendritic cells and modify the phenotype of the natural killer cell (Sotiropoulou et al. 2006). In 2012, Chen and coworkers demonstrated that AT-MSCs can be differentiated into astrocytes and neuronal-like cells (Chen et al. 2012). The transcriptional profile of AT-MSCs showed some similarity with BM-MSCs (Peroni et al. 2008). AT-MSCs also secrete various neurotrophic factors (Gutiérrez-Fernández et al. 2013; Yang et al. 2012). UC-MSCs can be also differentiated into neuron-like cells. Researchers studied these cells in mouse model having Alzheimer’s disease and clinically (Kang et al. 2016). Table 9.1 summarizes the studies of stem cell therapy on AD-diseased animal models.

Table 9.1 Outline of studies of stem cell therapy on Alzheimer’s-diseased animal models
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9.10 Some Clinical Trials of Stem Cell Therapies for Alzheimer’s Disease

Since 2011, animal model evidence supported the approval of MSC-based therapies in clinical trials for patients with Alzheimer’s disease. UC-MSCs were preferred, and the route of administration of stem cell is intravenous (Table 9.2).

Table 9.2 List of some main clinical trials of stem cell therapies for Alzheimer’s disease
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9.11 Conclusion and Future Prospects

Stem cell therapy exhibits therapeutic benefits in several neurodegenerative disorders. Stem cell transplantation increases the expression of synaptic protein markers in AD animal models. The transplantation of MSCs elevated the level of Aβ-degrading enzyme and reduced the level of Aβ due to microglial expression. With the ongoing development of reprogramming technology, there is an immense potential in the utilization of iPSCs in the treatment of AD. For reprogramming, somatic cells from patients could be used to generate iPSCs. After that, it can be differentiated into neural precursor cells for transplantation. This means that tissue rejections will never again an issue and there will be negligible ethical problems. Also, it can ameliorate the modeling of neurodegenerative diseases like AD, because iPSCs could differentiate into neurons, having the inimitable genetic phenotype of the patient. Thus, stem cell-derived neuronal cells create a cellular model which offers the closest relation to the sporadic form of the AD disease and expectantly translated into human studies to find a cure for the AD.