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The effect of the infection with Granulocyte-Macrophage colony-stimulating factor (GM-CSF) in the hippocampus of double transgenic animals for Alzheimer's Disease

Grant number: 14/17767-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2014
Effective date (End): October 31, 2015
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Beatriz de Oliveira Monteiro
Grantee:Yuri Letizio Di Giulio
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Dementia is turning into a big problem in the public health area, and the Alzheimer's Disease (AD) is the one that deserves the greatest attention. Progressive cognitive impairment, emotional disorders and the motor function deterioration are the major characteristics in the AD. The pathologic findings of the AD can be resumed in deposits of senile plaques made from amyloid-² protein (A²), neurofibrillary tangles of Tau protein and, as a consequence a disseminated state of inflammation in the Central Nervous System (CNS). These damages are generally found at areas of the brain that are linked to cognitive processes and memory. Although several advances have been made towards the understanding of the AD, we still lack an efficient treatment for this disease once our therapeutic options are resumed at easing the symptoms without curing the disease itself. In this way, it is crucial the search for new ways of treatment towards preventing the progression of the cognitive and motor impairment developing from the deposition of the amyloid-² plaques, of the neuronal degeneration and from the inflammation of the CNS. In this scenario, the use of viral vectors carrying genes for genic therapy presents itself as a promising alternative for the treatment of the AD. The Granulocyte-Macrofage Colony-Stimulating Factor (GM-CSF) is an important cytokine for the migration of cells from the white blood lineage towards the CNS and their subsequent differentiation into microglia with anti-inflammatory characteristics. Based on this idea, this new microglia of blood origin would be able to reduce the inflammatory state, softening the AD symptoms, a possibly cause the regression of the disease. In order to reproduce the effects of the AD in humans, several genetic modified models have been created. In this study, the model APPswe/PS1dE9, double transgenic for APP (APPswe: KM594/5NL) e PS1 (dE9: deletion of exon 9) will be used. This model reproduces the cognitive impairment, increase of the insoluble A² and neural degeneration. By using this model, we will investigate the potential of the overexpression of the gene GM-CSF in decreasing of the inflammation and neural degeneration besides the improvement of the cognitive function. Since the accumulation of the A² peptide and the neurofibrillary tangles lead towards an exacerbated state of inflammation and this set of factor lead towards neuronal and synaptic loss, the animals injected with the GM-CSF gene should present an increase of the migration of the cells from the blood lineage and their subsequent differentiation into microglia. This event should generate a significant improvement in the inflammation state that in turn should contribute for the reduction in the neural degeneration and consequently improve the cognitive impairment. The present study aims to investigate the regenerative mechanisms of APPswe/PS1dE9 and promises important therapeutic applications in the field of the dementia, especially at the Alzheimer's disease. (AU)

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