| Grant number: | 15/23426-9 |
| Support Opportunities: | Regular Research Grants |
| Start date: | March 01, 2016 |
| End date: | May 31, 2018 |
| Field of knowledge: | Biological Sciences - Physiology - Physiology of Organs and Systems |
| Principal Investigator: | Daniel Carneiro Carrettiero |
| Grantee: | Daniel Carneiro Carrettiero |
| Host Institution: | Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Santo André , SP, Brazil |
| Associated researchers: | Fernando Augusto de Oliveira Ribeiro ; Maria Camila Almeida ; Merari de Fátima Ramires Ferrari |
Abstract
The beta amyloid that comprises the extracellular senile plaques present in Alzheimer's disease is the product of the proteolytic cleavage of its full-length precursor protein, amyloid precursor protein (APP). Not much is known about the role of beta-amyloid in the healthy brain. Beta-amyloid function is crucial to development and tissue maintenance in the central and peripheral nervous system, growth cone formation and axon outgrowth, neural differentiation, and synaptic transmission.Beta-amyloid has both a neurotrophic and neurotoxic effect depending on the cellular context, as defined by poorly-understood cell signaling mechanisms. The neurotoxicity of Ab1-42, the 42 amino-acid beta-amyloid variant, is a differentiation-dependent effect, and while Ab1-42 is neurotoxic to differentiated neurons, it is neurotrophic to neural precursors. The mechanisms underlying this are poorly understood.Our lab has identified a gene, BAG2, which regulates the switch between beta-amyloid trophic and toxic effects. Overexpression of BAG2 in undifferentiated SH-SY5Y cells, which express low levels of BAG2, induced a diametric shift from trophic to toxic in response to Ab1-42, suggesting that BAG2 may be responsible for pathological activity of beta amyloid in Alzheimer's disease. Crucially, however, it is unknown if BAG2 expression in differentiated SH-SY5Y cells is necessary for the toxic effect of Ab1-42. Our research has shown that BAG2 expression is repressed by NF-kappaB. However, the identity of the NF-kappaB genes that regulate of BAG2 remains unknown.Further, evidence suggests that BAG2 regulates NF-kappaB post-translationally. BAG2 physically associates with the TNF receptor superfamily/NF-kappaB signaling complex, which activate either anti-apoptotic NF-kappaB signaling or pro-apoptotic JNK, as a consequence of beta amyloid interaction with p75NTR and DR6. The interaction between BAG2 and NF-kappaB/JNK suggests that it may influence Ab1-42-induced cell death. Thus, this grant laboratory proposal is based on further characterizing the cross-talk between NF-kappaB and BAG2 at the transcriptional and post-translational levels, utilizing the SH-SY5Y cell line and primarily hippocampal cell culture to investigate the molecular basis of the effect of the NF-kappaB/BAG2 axis on the differentiation-dependent neurotoxic effects of AB1-42 peptide trough qPCR, Western blotting, Imunoprecipitation, Immunofluorescent and flow cytometry Cell Analyzer techniques (AU)
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