Alzheimer’s extracellular aggregation of amyloid is a direct
Alzheimer’s disease is a debilitating neurological disorder, pathologically identified by the conglomeration of extracellular beta-amyloid plaques and neurofibrillary tangles within the brain. Individuals with Alzheimer’s disease exhibit a range of symptoms, spanning from mild cognitive impairment and language difficulties to more severe forms of psychosis, memory loss and emotional instability. While the underlying causes of this chronic illness remain undefined, misfolded oligomeric and monomeric forms of beta-amyloid play a significant role in pathogenesis. Similarly, pro-inflammatory neurofibrillary tangles also degrade neuronal function. These tangles are a product of heavily phosphorylated tau proteins which tend to group around neurons. The severity of Alzheimer’s disease has been closely linked with elevated oxidative stress. This elevated oxidative stress is a direct result of amyloid plaque formation, accelerated lipid peroxidation and the decline of mitochondrial function. Moreover, excessive oxidation of lipid and protein molecules were detected in AbPP/PS1 rodent test models which indicates to me that the presence of oligomeric amyloid fragments is related to the formation of reactive oxygen species (ROS). On the other hand, one could argue that the extracellular aggregation of amyloid is a direct result of proteolysis, rather than a by-product of reactive oxygen species. This is evaluated in the 2014 Butterfield report which illustrated how excessive protein and lipid oxidation in AbPP/PS1 rodents is similarly correlated with the activity of beta and gamma secretase enzymes. Considering that oxidative stress is hypothesised to be responsible for neurodegeneration, I believe that an antioxidant stem cell therapy should be able to effectively combat the stress-mediated, neurotoxic effects of reactive oxygen species.Mesenchymal stem cells have proven to be able to play a key role in reducing apoptosis and peroxidation. In particular, human umbilical cord mesenchymal cells can induce profoundly low levels of antioxidant enzyme activity as revealed in hypertensive rodents. The stem cells achieve this through decreasing the expression of ‘ROS-scavenging’ enzymes, including SOD and GPx. However, one could argue that human amniotic mesenchymal stem cells are better suited for neurodegenerative purposes as they do not exhibit the ‘histocompatibility complex class I’ molecule. In consideration I believe that the absence of this molecule would make them more tolerant of immune surveillance as this protein has been profoundly linked to cytotoxic T cell activation. To examine this idea further, in one study a colony of these stem cells were injected into transgenic (C57BL/6J-APP) mice modified to overexpress the APP gene. Following the transplant, tissue samples were analysed to determine the impact of the stem cells on beta-amyloid conglomeration. Promisingly, intraneuronal amyloid detection highlighted that amyloid plaque density decreased by an average of 22% in the cortex and 14% in the hippocampus (see Fig.2); two main regions which suffer from cholinergic neuronal death. While this is initially promising, I think that it is vital to evaluate the effects of the therapy on spatial memory performance. To achieve this, the mice were subjected to water-maze acquisition testing 3 weeks post-transplantation. In comparison with the control group, I think it is notable how the test rodents displayed a large increase in spatial processing abilities with P value of less than 0.01(see Fig.3). Considering that this result is statistically significant, in my view this study strongly validates the hypothesis that amyloid plaque formation is correlated with a decrease in cognitive function . Comparatively, these sets of results illustrate how human amniotic mesenchymal stem cells can be applied to treat both the initial conglomeration of amyloid plaque in the cortex, and be adopted as a preventative measure to reduce the production of ROS and other peroxide species. The activity of SOD also showed signs of decline as amyloid concentration decreased, providing more evidence to support the oxidative stress-hypothesis. This study has made me question if neurogenesis is also a feasible outcome for patients. To understand the mechanism of neurogenesis, it is important to understand the relationship between neurons and glial cells. Within the brain, the glia and microglia modulate synaptic plasticity and produce a plethora of cytokines which inhibit axonal renewal, such as Interleukin-1 and Tumour Necrosis Factor-Alpha. Conversely, other studies have revealed that ‘alternate microglia’ of the M2 derivative can play a neuroprotective role through secreting neurotrophins and stimulating the phagocytosis of amyloid fragments. In order for neurogenesis to occur in Alzheimer’s disease patients, I predict that stimulating these ‘alternate’ microglia could establish the ideal neuro-environment. This leads me to comment on one study in which researchers aimed to develop mesenchymal-derived neural cells with the function of activating M2 microglia in order to modulate neuroinflammation.Following the transplant, the cerebral cortex and hippocampus were removed and subjected to immunocytochemical testing. This analysis reveals that 86.42% of the transplanted stem cells expressed increased levels of the biomarkers MAP2 and GFAP. From this, I can infer that stem cells successfully formed microtubules and thus integrated into the central nervous system. However, one should remain cautious of the increased levels of neuron-specific enolase that were also detected in the same neural cells. This specific glycolytic enolase is primarily recorded in patients exhibiting neuronal damage, as well as in up to 70% of patients suffering from neuroblastomas and neural crest-derived tumours. The presence of NSE-secreting neurites could be indicating early tumour metabolic activity and potentially uncontrollable stem cell division. In evaluation, I argue that the detection of glycolytic enolase would significantly hinder the clinical viability of this therapy despite the encouraging detection of key neural biomarkers.With regard for neurogenesis, one must also consider that the stem cell derived-neural cells were successful in promoting M2-microglia activation. In fact, the neural cells stimulated a significant up-regulation of Interleukin-4 in vivo, activating local microglia to assume a M2 function. Similarly, PCR analysis also revealed that this stem cell therapy initiated the down-regulation of TNF-alpha and other major proinflammatory cytokines. I think that these findings collectively support the initial hypothesis that HUMSC-neural cell transplantation could reduce chronic inflammation within Alzheimer’s patients. Moreover, the rodent models were experimented on without the introduction of immunosuppressants. Therefore one could conclude that the stem cells were able to withstand immune system inspection across the entire course of the therapy due to their lack of the surface antigens CD40, CD80 and CD86. Considering this result, from my perspective human umbilical cord stem cells would be well tolerated for xenotransplantation into dementia patients and could prove very useful for establishing a M2-mediated neuroprotective environment in which neurogenesis can be induced.