NF-kappaB and BAG2 Regulation of Beta-amyloid Mediated Neuronal Cell Death

• Grant number: 15/14985-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2015
• End date: January 31, 2016
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Daniel Carneiro Carrettiero
• Grantee: Fernando Enrique Santiago
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

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 Abeta1-42, the 42 amino-acid beta-amyloid variant, is a differentiation-dependent effect, and while Abeta1-42 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 Abeta1-42, 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 Abeta1-42. 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 Abeta1-42-induced cell death.Thus, this grant 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 to investigate the molecular basis of the effect of the NF-kappaB/BAG2 axis on the differentiation-dependent neurotoxic effects of Abeta1-42 peptide.