Alzheimer's disease (AD) is the most prevalent type of dementia, it is related to age, sex, apo-lipoprotein E genotype (ApoE), and amyloid precursor protein (APP) degradation products (Supnet and Bezprozvanny 2010; Ana et al., 2012; Xiao et al., 2014). AD is characterized by its progression, neurobehavioral and neuro-pathological alternations; the diverse neuronal loss throughout the basal forebrain, hippocampus, amygdala, and cortical area (Xiao et al., 2014). The neurobehavioral alterations including short-term memory loss in early stage, are manifested by confusion, aggression, mood swings, long-term memory loss, and social isolation in advanced stages, causing social as well as economic issues in addition to public health disturbance (Thenmozhi et al., 2015). Neurotransmitters have neuroprotective special effects versus dementia. There are numerous associated abnormalities in various systems of neurotransmission in AD like in noradrenergic, cholinergic, and dopaminergic systems (Aliev et al., 2019). In 2015, there were about 47 million people with AD and it's a predicted that this number will reach about 131 million by 2050 (Prince 2015).
Pathologically, AD has two major hallmarks which are insoluble extracellular β-amyloid AB accumulation in senile plaques and intracellular tau-protein filaments in the form of neurofibrillary tangles NTFs (Koo et al., 2013). The pathological amyloid peptide oligomer is produced from amyloid precursor protein (APP) which is a transmembrane protein after a sequence of proteolytic effects of b- and c-secretases (Thenmozhi et al., 2015). So, AD can be defined as irreversible cognitive function deterioration based on forebrain neuron loss of cholinergic projection system in the nucleus basalis of Meynert (nbM) mainly, due to extracellular accumulation of insoluble Aβ protein.
There are no consent measures to definitely diagnose and regulate development of AD (Cure et al., 2014) and this significantly obstructs effective treatments versus AD. To examine AD pathologies and its targets, various animal models of AD have been used in preclinical settings. The use of animal models has enabled scientists to investigate many diseases on different levels including behavioral, physiological, cellular and molecular mechanisms of Alzheimer's progression (Gotz and Ittner 2008; Jour et al., 2011). In addition, animal models could be used for some tests that could be done only in animals rather than human, to evaluate the primary effect of different agents including protective and therapeutic (Esquerda et al., 2017). Among these, mice and rats are extensively used, and their transgenic complements are the most-established system to assess disease pathophysiology in addition to successful treatment strategies (Bali et al., 2017). Rats are the most commonly used animal models due to their large size and body dimensions in addition to manipulation easily (Esquerda et al., 2017).
Aluminum (Al) has a vital role in AD pathogenesis and etiology as a neurotoxic metal (Cao et al., 2017), depending on clinical studies and many documented in vitro and in vivo (Thenmozhi et al., 2015). Previous studies showed that Al accelerates extracellular AB oligomers generation and deposition (Cao et al., 2017; Thenmozhi et al., 2015). Al is also acting as a cholino-toxin affecting the cholinergic activity, a main hallmark of AD neurochemistry (Thenmozhi et al., 2015). Aluminum reaches the brain through blood brain barrier (BBB) via different routes such as diet, cosmetics, medications, toothpaste, drinking water and fumes inhalation. This led to its deposition in the cortex, cerebellum and hippocampus causing memory deterioration and triggers cognitive decline. In another word, AD was inducted via AB accumulation after oligomerization and tau phosphorylation and aggregation in addition to apoptosis, impaired calcium ion exchange, and lipid peroxidation (Thenmozhi et al., 2015).
Aluminum was reported in clinical trials to present in an extremely higher levels in sporadic and familial AD brain tissues accounting for 10 pg/g tissue dry weight in 5/12 patients, comparing to normal ones. Additionally, it is believed to initiate an AD like inflammation, as it induces the formation of fibrillary depositions, which is almost similar to neurofibrillary tangles, causing an adverse effect on memory and recognition abilities, causing extra oxidative stress. Therefore, it was used to create a model which mimic the AD brain, AlCl3 which is a common form of Al (a major risk factor of AD).
Moreover, Al-induced rat model of AD is an established model widely used to investigate the etiology and treatment strategies of the disease (Cao et al., 2017). To evaluate cognitive impairments in animal models, some behavioral tests were adopted including T-maze tasks, due to its sensitivity to memory deficits and hippocampal-dependent learning (Lee et al., 2018).
The etiology of AD is not clearly defined. There is a relationship between AD and apoptosis with p53 being up-regulated, and Bcl-2 being down-regulated (Paradis et al., 1996). Bcl-2 overexpression might have a potential role in preventing the aggregation of β amyloid plaques and the following cell death by reducing β amyloid through the activation of p38 MAPK and NF-κB pathway (Song et al., 2004)
The recently used treatments for AD have limited curative abilities, so finding a cure is a critical challenge that faces scientific research. One of the most successful therapeutic strategies is immunotherapy which used monoclonal antibody to reduce amyloid-β aggregates, and upon that success, some of them has reached phase III in clinical trials such as solanezumab and gantenerumab (Cummings et al., 2017). These treatments can improve symptoms, however; they cannot stop AD progression, and they only offer symptomatic relief with some side-effects (Xiao et al., 2014).
Stem cell therapy in regenerative medicine is one of the promising approaches aiming to help in treating neurodegenerative diseases especially AD (Kim et al., 2012). There is no doubt that selecting the best source of stem cells has a vital role in transplantation therapeutic efficiency. Adipose-derived mesenchymal stem cells (ADMSCs) are reported for their effective therapeutic and preventive potentials in regenerative medicine and stem cell-based therapy. ADMSCs are involved in different in vivo and in vitro studies to examine their multipotency, and safety. However, there is no equivalent established clinical trials in stem cell- based therapy depend on it (Kim et al., 2012).
Taurine is a free sulfur amino acid that shows intercellular and intracellular abundance in mammals. However, it is not incorporated in any protein synthesis, it is a key element in many physiological processes such as osmoregulation and bile acid conjugation, pharmacological actions, pathological states and prevention of oxidant-induced injury in many tissues (Yildirim et al., 2011). In biological systems, taurine acts as an antioxidant via stabilizing bio-membranes, scavenging ROS, and reducing the peroxidation of unsaturated membrane lipids (Yildirim et al., 2011).
Taurine is suggested to be a key element in neurotransmission, neuromodulation, osmoregulation, control of calcium influx, and cell excitability. Taurine also has the ability to pass the BBB via β amino acid transporter TAUT, that so called Taurine Transporter (Gebara et al., 2015). Taurine is 3–4 times more represented in a developing brain than an adult one (Trevor et al., 2000), however, it declines gradually with aging (Banay-Schwartz et al., 1989). So, taurine is suggested to participate in the development of brain, and insufficient dietary taurine in gestation causes the visual cortex and cerebellum to develop inappropriately in newborn cats (Gebara et al., 2015). It also enhances memory and hippocampus-dependent learning, and alleviates anxiety and depression (Si et al., 2004). Taurine was found to enhance stem cell activation and propagation yielding a higher concentration of neural progenitors and stem cells, and aid to lessen the number of activated microglia leading to down-regulated inflammation. (Gebara et al., 2015). It was reported to enhance the propagation of adult neural stem/progenitor cells in vitro (Gerardo Ramos-Mandujano et al., 2014; Reyna Hernandez-Benitez et al., 2012). In view of the above-mentioned correlation of ADMSCs and taurine in treating AD, the present study aims to investigate the possible therapeutic effects of ADMSCs and/or 2-taurine on neurodegeneration in male rat model of AD, in order to introduce approved pre-clinical study that can be used in the future for advanced clinical studies.