Stem cells in the treatment of neurodegenerative diseases (3)

(Continued; the beginning of the article is here.)

Alzheimer's disease and stem cells

Alzheimer's disease is one of the main causes of senile dementia [26]. This disease, the fundamental markers of which are plaques formed in the brain tissue from beta-amyloid peptide and neurofibrillary cords [21,27-29], leads to the death of several types of nerve cells in many regions of the brain [29-31], especially cholinergic neurons [23]. Discovered in 1987, the amyloid precursor protein gene is located on chromosome 21 and encodes a type I transmembrane protein [32].

Plaques from beta-amyloid are formed as a result of the cutting of the amyloid precursor protein, carried out by the enzymes gamma- and beta-secretases between certain amino acids [33]. Neurofibrillary strands consist of hyperphosphorylated tau proteins [34]. The formation of these structures leads to damage to neurons and, accordingly, to deterioration of cognitive function and memory loss [29]. However, researchers have not yet been able to decipher the direct mechanisms of the pathogenesis of Alzheimer's disease [35].

Currently existing drugs for the treatment of Alzheimer's disease, such as cholinesterase inhibitors [33,37], allow only to stop the symptoms of the disease [36]. After the release of the neurotransmitter acetylcholine from the synapse, cholinesterase inhibitors slow down its degradation, which has a beneficial effect on cognitive function [33]. However, drugs of this type have only a moderate effect, the severity of which may vary for different patients [38].

The active substance of another type of available drugs for the treatment of Alzheimer's disease is the N-methyl-d-aspartate receptor antagonist memantine [33]. It prevents excessive stimulation of N-methyl-d-aspartate receptors, which may have a toxic effect [33]. Considering that modern methods of treatment have weak effects, the severity of which varies significantly in different patients, there is an urgent need for new therapeutic approaches. According to statistical forecasts, by 2029, 615,000 new cases of Alzheimer's disease will be diagnosed annually in the United States, and by 2050 – 959,000 new cases of Alzheimer's disease [26]. Such an increase in morbidity will increase the burden on the healthcare system [26].

Recently, Blurton-Jones et al. [29] published the results of a study in which they injected neural stem cells into the hippocampus of transgenic mice with an Alzheimer's disease model and ordinary animals of the same age. An interesting fact is that the procedure improved the cognitive function of mice without having any effect on the existing beta-amyloid plaques and neurofibrillary cords [29]. Instead, researchers identified an increase in the level of neurotrophic brain factor in the brain of animals, which plays an important role in the formation of new neurons and synapses [39], which contributed to the improvement of cognitive function by increasing the density of synapses [29]. This demonstrates the possibility of improving cognitive function without interfering with existing pathological manifestations [29].

Despite the fact that the physiological function of the amyloid precursor protein is unclear, recently published data indicate that it may play an important role in regulating the biological functions of stem cells or adult neurogenesis [40]. The authors found that the amyloid precursor protein increases chemokine levels, which affects cell migration [41]. It has also been shown that an increase in the level of the amyloid precursor protein triggers the differentiation of human neural stem cells into glial cells both in vitro and in vivo. This can complicate the process of regeneration of neurons by stimulating the division of nerve stem cells against the background of a high concentration of amyloid precursor protein. Moreover, high levels of amyloid precursor protein detected in patients with Down syndrome who develop Alzheimer's disease during their lifetime can deplete endogenous populations of nerve stem cells due to their increased premature differentiation into glial cells [42]. This function of the amyloid precursor protein, apparently, should be taken into account when developing therapies for neurodegenerative diseases with elevated concentrations of this protein in the brain of patients. Elevated levels of amyloid precursor protein in the brain not only reduce the population of neural stem cells, which may increase the risk of developing Alzheimer's disease, but also stimulate glial differentiation of transplanted stem cells, reducing the effectiveness of therapy aimed at improving cognitive function [42,43]. Thus, in certain cases, before stem cell transplantation, it is advisable to reduce the level of amyloid precursor protein in the brain. This is confirmed by the results of experiments on transplantation of neural stem cells to transgenic mice with increased expression of this protein in the brain, the concentration of which was reduced using fenserin [34]. Neural stem cells can also have a positive effect by increasing the concentration of growth factors. A transgenic model of Alzheimer's disease has been shown to improve cognitive function due to the release of brain neurotrophic factor after nerve stem cell transplantation [29]. The ability of these cells to express brain neurotrophic factor and stimulate axon growth has also been demonstrated in a model of spinal cord injuries [44].

Many experimental studies demonstrate a positive neuroprotective effect of hematopoietic growth factors, such as granulocyte colony-stimulating factor, erythropoietin, granulocyte-macrophage colony-stimulating factor, stem cell factor, vascular endothelial growth factor and factor-1-alpha stromal cells, in ischemic stroke [45,46]. In an animal model of transient ischemia, the ability of mesenchymal stem cells isolated from the bone marrow to protect the brain from ischemic damage or to reduce their consequences by releasing insulin-like growth factor-1 was shown [47]. Despite the promising results obtained in animal model studies, the lack of clinical data makes it difficult to assess the effectiveness of the use of growth factors as a therapy for neurodegenerative diseases. In a clinical study involving stroke patients, the introduction of mesenchymal stem cells provided a pronounced stable improvement in the Barthel index and the modified Rankine scale compared with patients in the control group during a follow-up period of 12 months [48]. After that, a long-term catamnestic study of the results of intravenous administration of autologous mesenchymal stem cells to patients with ischemic stroke demonstrated very encouraging results [49]. The results obtained in the future may help in the development of methods for using stem cells to increase the levels of growth factors in Alzheimer's disease.

Continuation: Parkinson's disease and stem cells.

Portal "Eternal youth" http://vechnayamolodost.ru30.03.2012