**Abstract**

Alzheimer's disease (AD) is a kind of neurodegenerative disease with insidious onset and progressive progression. The etiology of AD may be related to the loss of neurons, astrocytes, and microglial in the nervous system. Exogenous stem cell transplantation has brought hope to the treatment of AD. Stem cell transplantation can reduce amyloid β-protein (Aβ) deposition and Tau phosphorylation, and provide secretory factor support to improve learning and memory deficits. The purpose of this review is to provide an overview of the relationship between different stem cell species and the treatment of AD, and also summarize current experimental stem cell therapy strategies and their potential clinical applications in the future.

**Keywords:** Stem cells, Therapy, Alzheimer's disease (AD)

### **1. Introduction**

According to the World Alzheimer Report 2019, more than 50 million people worldwide suffer from dementia. It is expected to grow to 152 million by 2050. The current cost of treating dementia is \$1 trillion a year, and that cost is expected to double by 2030. There are more than 200 subtypes of dementia, of which 50 to 60 percent are caused by Alzheimer's disease (AD). The concept of the disease was proposed by Alois Alzheimer in 1907. It was later recognized as the most common neurodegenerative disease. Although decades have passed since the discovery of the pathological mechanism of Alzheimer's disease, we still do not know what causes the disease. It is well known that Alzheimer's disease is a sporadic, age-related disease, with only a small proportion caused by genetic factors. The disease is characterized by a progressive decline in cognitive function. Clinically, these patients present with short-term memory impairments that interfere with activities of daily living, followed by impairments in other cognitive areas such as language, logical understanding, orientation, executive function, judgment, behavior, and finally motor impairments [1]. The pathological features of AD include: Senile Plaques (SP) formed by the deposition of amyloid β-protein (Aβ) outside neurocyte; The abnormal phosphorylation of intracellular Tau protein results in the neurofibrillary tangles (NFTs); Synaptic loss, neuroinflammation, neurocyte apoptosis in the neocortex and hippocampus of the brain. The pathological manifestations were brain atrophy [2–5]. In this review, we believe that the most effective strategies should target the biological feature which is most associated with symptoms, the loss of synapses, to treat the disease. Specifically, we focus on recent advances in cellbased therapies that aim at repopulation or regeneration of degenerating neuronal networks in AD [6].

## **2. Alzheimer's Disease's neuropathology**

As mentioned in the background, we group the pathological changes of Alzheimer's disease into two types, which provide evidence of the disease's occurrence and progression: (1) Positive lesions. The main findings include SP caused by Aβ deposition and NFTs caused by abnormal phosphorylation of intracellular Tau protein. Otherwise, dystrophic neurites, neuropil threads and various other sediments found in the brains of patients with AD also falls into this category. (2) Negative lesions, which can also called loss type lesions. The main clinical manifestation is brain atrophy due to loss of synapses. At the same time, other factors, including neuroinflammation, oxidative stress, and damage to cholinergic neurons, are all important factors leading to the occurrence of neurodegenerative diseases.

### **2.1 Senile plaques (SP)**

The SP are extracellular deposits of Aβ with different morphological forms, including neuritic, diffuse, dense-cored, or classic and compact type plaques [5].

The formation of Aβ is from the amyloidogenic cleavage of human amyloid precursor protein (APP) [7]. The anomalous processing of APP by β-secretases and γ-secretases leads to production of Aβ40 and Aβ42 monomers, which further oligomerize and aggregate into SP [8, 9]. Although soluble Aβ40 is much more abundant than soluble Aβ42, Aβ42 exhibits a higher propensity for aggregation, due to hydrophobicity within its two terminal residues. Indeed, Aβ42 is the main component of amyloid plaques and is shown to be neurotoxic [10]. Recent neuroimaging and neuropathology researches reveal that Aβ sedimentation is mainly related to cognitive disorder of the old, and it is not very relevant with other clinical features [11].

### **2.2 Neurofibrillary tangles (NFTs)**

Tau protein is mainly distributed in neurons. Repeated Pro-Gly-Gly-Gly fragments help it bind to tubulin and maintain the structural stability of microtubules. The presence of Tau protein contributes to the maintenance of cytoskeleton and the integrity of axon transport [12]. NFTs are filamentous structures filled in the cytoplasm of neurons -- paired helical fibers (PHF). The reason of Tau hyperphosphorylation is the increased protein kinase activity. Protein kinase activity such as glycogen synthase kinase 3β (GSK-3β) activity can be decreased to reduce phosphorylation. Meanwhile, decreased phosphatase activity is also the reason of hyperphosphorylation. In addition, the lack of glucose in the brain can make Tau hyperphosphorylated by mediating the signal pathway of p38 mitogen-activated protein kinase (MAPK). Increasing the level of glucose in the brain may provide a new idea for treating AD, by using a pharmacological model of glucose deprivation and investigated its effect on Tau phosphorylation, synaptic function and cognition in a relevant transgenic mouse model of tauopathy, the h-Tau mouse [13]. It has been shown that phosphorylation of Tau protein at the early stage of AD inhibits Aβ toxicity, being that Tau phosphorylation-mediated by p38 MAPK can antagonize the postsynaptic excitation toxicity caused by Aβ [14, 15].

### **2.3 Synaptic loss**

Soluble Aβ collaborate with pTau to induce synapse loss and cognitive impairment in AD [16]. Metabolism of Aβ and Tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy [17]. Neuroplasticity *New Prospects for Stem Cell Therapy in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.100334*

is an ongoing process that responds to the activity, injury, and death of neurons, including the regulation of the structure and function of axons, dendrites and synapses [18]. Overdeposition of Aβ and abnormal phosphorylation of Tau both lead to decreased neuroplasticity, which is manifested in a series of clinical symptoms caused by synaptic loss in AD [12, 19]. Aβ and Tau both trigger mitochondrial alterations. Some evidence suggests that mitochondrial perturbation acts as a key factor that is involved in synaptic failure and degeneration in AD [20]. Synaptic plasticity and long-term potentiation (LTP) are all about N-methyl-D-aspartate receptor (NMDAR). Aβ oligomer facilitates astrocytes (AS) to release glutamate by a7nAChR and activates NMDAR, making extracellular regulated protein kinases (ERK) signaling pathway to be suppressed and finally suppressing LTP, therefore the synaptic damages caused by NMDAR hyperactivation are the possible mechanisms of AD occurring [21].

### **2.4 Neuroinflammation**

The AD pathophysiology entails chronic inflammation involving innate immune cells including microglia, astrocytes, and other peripheral blood cells. Inflammatory mediators such as cytokines and complements are also linked to AD pathogenesis [22, 23]. Activation of microglia can induce the production of inflammasomes, which in turn increase inflammatory cytokines, and may eventually result in Aβ deposition [24, 25]. Studies have shown that after being activated, astrocytes will release the corresponding cytokines, which can lead to the enhancement of neuronal toxicity, as well as a decreased outgrowth of neuronal processes and an overall decreased activity rate [26]. Recent studies have shown that there is a direct interaction between microglia and astrocytes. In the form that once microglia are activated, they can lead to activation of astrocytes, thus forming feed-forward loops that are harmful to the surrounding environment [26]. The mechanism showed that when being activated, microglia release IL-1α, TNFα and C1q and astrocytes become activated. Microglia and astrocytes are major modulators of inflammation in the brain, and they are also the major sources of apolipoprotein E (ApoE) in the brain. ApoE is a multifunctional protein with central roles in lipid metabolism. It transports lipids, including cholesterol, through the cerebrospinal fluid (CSF) and plasma [27, 28]. Earlier studies have shown that the presence of ApoE helps to inhibit glial activation of lipopolysaccharides in glial cell culture experiments, suggesting that ApoE may exert a protective anti-inflammatory effect [29, 30]. Moreover, the exacerbated proinflammatory state that occurs during this period of AD can trigger the hyperphosphorylation of Tau. Several of the kinases responsible for Tau phosphorylation are activated by proinflammatory mediators and have been shown to worsen Tau pathology [31].

### **2.5 Cholinergic neurons' injuries**

The Acetylcholine (ACh) receptor (AChR) is a vital membrane protein on which ACh acts as a neurotransmitter. The cholinergic receptors are broadly categorized as muscarinic ACh receptors (mAChR) and nicotinic ACh receptors (nAChR) on the basis of their exogenous agonists [32]. ACh plays an important role in human memory function and is strongly associated with age-related dementia such as AD, in which hippocampal dependent learning dysfunction is prominent. Cholinergic neurons densely dominate the hippocampus and mediate the production of episodic and semantic memory [33]. In patients with AD, the synthesis, release and uptake of ACh in the hippocampus, neocortex and cerebrospinal fluid were decreased, the choline acetyltransferase (AChE) was significantly decreased, and the activity of

acetylcholinesterase was decreased [34]. Clinically, the main method of drug treatment for AD is to improve the function of the brain's cholinergic system. Although inhibitors of acetylcholinesterase is a symptomatic relief treatment with marginal benefits, it is currently the most available clinical treatment which gives desperate AD patients a glimmer of hope [35].
