Effect of stem cell overexpressing NGF transplantation in double transgenic model of Alzheimer's Disease

• Grant number: 12/09572-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2012
• End date: June 30, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Beatriz de Oliveira Monteiro
• Grantee: Daisyléa de Souza Paiva
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated scholarship(s): 14/10312-2 - Genome-wide analysis of reactive astrocytes in Alzheimer's Disease and other two types of central nervous system injury, BE.EP.DD

Abstract

Alzheimer's disease (AD) is the most common type of dementia and is characterized by progressive deficits in cognitive function and emotional disorders, resulting from selective neuronal dysfunction, synaptic loss and death of neurons. Its pathological changes typical of AD include senile plaques composed of extracellular deposits of amiloyd-² (A²) and neurofibrillary tangles formed by accumulation of abnormal filaments of Tau protein. Generally, these lesions are found in brain areas linked to cognitive functions and memory. Although many advances in the understanding of AD, there is still a lack of effective treatment, since the available options only promote the attenuation of the symptoms, but don't provide the cure. Therefore, there is a great interest in developing new therapies which could regret or prevent the progression of cognitive impairment caused by deposition of A² plaques and neuronal degeneration. In this scenario, the use of neural stem cells carrying vectors for gene therapy present as a promising alternative. Nerve Growth Factor (NGF) is a crucial neurotrophin crucial for survival and neuronal plasticity and its involved with learning and memory, and its deficiency may be related to the development of the AD. In order to reproduce the pathological effects of human AD, various geneticallty modified animal models were created. In this study, we will use the APPswe/PS1dE9, double transgenic mutant for APP (APPswe: KM594/5NL) and PS1 (dE9: deletion of exon 9), that reproduces the cognitive impairment, increased levels of insoluble A², and neurodegeneration. Using this model, we will investigate the potential of neural stem cell (NSC) transplantation in the recovery of cognitive function and neuronal regeneration and the effect of overexpression of NGF by NSCs in the reduction of senile plaques, neuronal repopulation, and improvement of cognitive function. Since the accumulation of A² leads to the neuronal and synaptic loss, animals transplanted with NSC-NGF must present memory improvement, reduce the levels of A², as well as the release of factors that promote tissue reapairment and functional improvement. This research should help to understand the role of NSC in regenerative mechanisms in the brain of APPswe/PS1dE9 animals, and promises important therapeutic interventions in aging and neurodegeneration. (AU)