Stem cells and neurodegenerative diseases (3)

Stem cells and Alzheimer's disease

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Alzheimer's disease (AD) is described by the German psychiatrist Alois Alzheimer (Alois Alzheimer) It is known as "presenile dementia" and is one of the most common neurodegenerative diseases worldwide. It is the leading cause of dementia in an aging population and has recently been identified as the sixth leading cause of death. Patients with Alzheimer's disease suffer from cognitive impairment, memory loss and behavioral changes, the root cause of which is neurodegeneration. The hippocampus, amygdala, neocortex and basal regions of the forebrain are adversely affected by the disease, which is the cause of impaired cognitive function and memory. The pathological manifestations of Alzheimer's disease include neurofibrillary cords and beta-amioid plaques. Excessive phospholyrization of tau protein and aggregation of amyloid peptide, respectively, leads to the formation of neurofibrillary strands and beta-amyloid plaques. Genetic causes of Alzheimer's disease include mutations of presenilin-1 (PSEN1), presenilin-2 (PSEN2), amyloid precursor protein (APP) and apolipoprotein E. Currently, there are no drugs that cure this disease, temporary relief can be achieved only with the help of acetylcholinesterase inhibitors. Drugs of this class include takrin and its derivatives, donepizel, rivastigmine, galantamine and the glutamine receptor agonist memantine. These pharmacological interventions approved by the US Food and Drug Administration (FDA) provide only symptomatic relief for a short time, while in the long term they may have undesirable side effects. Supposedly an effective approach to the treatment of Alzheimer's disease is the removal of beta-amyloid plaques from brain tissue. There is evidence according to which the enzyme neprilysin is involved in the process of cleaning brain tissue from plaques. A similar role is played by other proteinases, such as cathepsin B and plasmin, which are considered potential powerful therapeutic agents against Alzheimer's disease. The results of a number of earlier studies have demonstrated the feasibility of using nerve growth factor to prevent neurodegeneration and amyloid toxicity, however, this approach has a very serious limitation, since the factor molecules are not able to cross the blood-brain barrier and therefore are not suitable for peripheral administration.

Transgenic animal models of Alzheimer's disease, carrying mutations associated with the disease, provided a large amount of information on its etiology and pathophysiology, but did not allow us to understand the relationship between nerve growth factor and the formation of amyloid plaques. Mouse models today do not allow to fully reproduce the pathophysiology of human disease and failures of clinical trials of drugs that have demonstrated effectiveness in experiments on mice have already been reported. Earlier studies have demonstrated that implantation of genetically modified fibroblasts into the forebrain of patients provided suppression of neurodegeneration and restoration of cognitive function disorders associated with Alzheimer's disease. Whereas fibroblasts are inherently immobile and unable to migrate to other regions of the brain, transplanted stem cells can migrate to release growth factors into damaged regions of the brain. Thus, positional stem cell transplantation therapy may be more fruitful in this case.

Numerous publications describe the successful use of stem cell transplantation strategies in Alzheimer's disease. One of these studies demonstrated that when transplanted to mouse models of Alzheimer's disease, neural stem cells derived from embryonic stem cells provide better results compared to embryonic stem cell transplantation. The transplanted neural stem cells remained stable and successfully differentiated into cholinergic neurons, which provided improved memory. On the other hand, control group animals that underwent embryonic stem cell transplantation developed teratomas. Another study was conducted on a mouse brain expressing aggregates of amyloid plaques and neurofibrillary strands. Genetically modified neural stem cells expressing the neurotrophic factor of the brain were successfully transplanted into the brains of rodents, which improved learning ability and memory. Such neural stem cells did not reduce the number of amyloid plaques, instead, an increase in the levels of the brain's neurotrophic factor contributed to the formation of new synapses.

Stem cells and iPSCs are widely used to study human-specific reactions and comprehensive study of Alzheimer's disease. In 2011, Yagi et al. for the first time, neurons were obtained from the iPSC of a patient carrying mutations of the PSEN2 and PSEN1 genes. Since then, a number of studies have used this approach of patient-specific modeling of Alzheimer's disease using iPSCs. The catalytic subunit of the gamma secretase enzyme is encoded by the PSEN1 gene, mutations of which lead to the manifestation of the early stages of familial Alzheimer's disease. Stem cell models of the disease as a whole are aimed at elucidating the role of involvement of gamma secretase activity in the development of sporadic and familial forms of Alzheimer's disease. For example, the results of the studies showed that the ratio values of different forms of beta-amyloid (Aß42/40) were higher in neurons obtained from iPSC patients (fibroblasts with PSEN1 mutations), compared with control group cells. Similarly, mutations of the amyloid precursor protein led to an increase in the Aß42/40 ratio in human forebrain neurons. In several studies, familial Alzheimer's disease was modeled using iPSCs carrying mutations of the amyloid precursor protein, such as dominant V717L and recessive E9636 mutations. A study by Israel et al. It has been demonstrated that inhibition of gamma- or beta-secretase activity leads to a decrease in amyloid-beta-40 production, whereas inhibition of gamma-secretase does not prevent phosphorylation of tau proteins.

Stem cell-derived neurons and astrocytes are widely used for in-vitro modeling of familial Alzheimer's disease. Gene mutations lead to obvious changes in the cellular phenotype, such as changes in beta-amyloid. However, the way in which the processing of the amyloid precursor protein is interconnected with the phosphorylation of the tau protein is an aspect that cannot be effectively modeled today. The onset and initiation of Alzheimer's disease is mainly explained by the amyloid hypothesis. The amyloid precursor protein is a bitopic (once crossing the membrane) transmembrane protein, the proteolytic cleavage of which leads to the appearance of short beta-amyloid peptides. Mutations of genes involved in the proteolysis of the amyloid precursor protein play a key role in the development of familial Alzheimer's disease. Beta-amyloid-42 is a longer form of the peptide, the accumulation of which causes neurodegeneration and cell death. Posttranslational changes, as well as changes in the intracellular localization of the tau protein associated with microtubules, play the second most important role in the progression of Alzheimer's disease. With joint modeling, tau protein changes and aggregation of amyloid plaques on stem cells provide the best models of Alzheimer's disease. Simple monogenic neurons obtained from iPSCs are not enough to simulate amyloidosis, since they accumulate low levels of toxic beta-amyloid plaques. To overcome this difficulty, stem cell lines carrying multiple mutations were created, as well as demonstrating the overexpression of mutated genes, such as the amyloid precursor protein (APP) gene and PSEN1.

Continuation: Stem cells and Parkinson's disease

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28.02.2017