Evaluation of hippocampal transplantation of mesenchymal stem cells for treatment of Alzheimer's Disease in animal model

Abstract

Alzheimer's disease (AD) is clinically characterized by a progressive loss of memory, learning and behavioral dysfunction and changes in social interactions. The presence of extensive deposition of ²-amyloid peptide (A²) in the form of senile plaques and the neurofibrillary tangles in the cortex and hippocampus, along with neuronal and vascular damage, are the main characteristics of the AD pathology. In addition, AD is strongly associated with inflammatory processes by microglial and astrocytic reaction resulting in neurotoxicity.In recent years, it has been focused a great deal of interest in studies on the potential of mesenchymal stem cells (MSC) as a therapeutic resource for several neurodegenerative diseases. MSC may have important implications in the modulation of inflammation and degeneration present on the aging process and the development of AD. Recent evidence of indicate that the transplantation of MSC is able to promote local functional improvement, promoting neurogenesis, reduction of amyloid-beta plaques and reducing inflammation in AD (Garcia et al., 2014). In addition, the transplantation of MSC presents itself as a promising alternative for treatment of some diseases since these cells may be used for the overexpression of genes of interest inserted by viral vectors. Thus, the MSC, potentiated or not by high expression of genes with anti-inflammatory and neuroprotective actions, could prevent or attenuate the main symptoms of the AD, promoting the reduction of inflammation, and consequently, contributing to the clearance of the ² peptide and improving the clinical state of cognitive deficit. By the use of the double-transgenic mice model for AD, the APPswe/PS1dE9 (2xTg/DA), our study proposes to investigate the potential of MSC in decreasing inflammation and neurodegeneration, as well as the improvement of cognitive function. For this, the animals will be transplanted in the hippocampus with MSC, modified or not with viral vectors for the overexpression of SDF1 and GM-CSF, and will be tested for behavioral learning and memory tasks, and their brains will be analyzed to assess the A² plaques, levels of cytokines, quantification of microglia and neurogenesis. This project should contribute with important therapeutic implications in aging and neurodegeneration in Alzheimer's disease, in addition to explaining the effects of mesenchymal stem cells and chemokine SDF-1 and cytokine GM-CSF in the pathophysiology of the AD. (AU)