Crosstalk between BAG2 and NF-kappaB mediated by Beta-amyloid: Importance for Alzheimer Disease?

• Grant number: 16/09762-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2017
• End date: June 30, 2018
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Daniel Carneiro Carrettiero
• Grantee: Ramon Torreglosa Do Carmo
• Host Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Santo André , SP, Brazil

Abstract

Alzheimer's disease, the most common form of neurodegenerative a disorder affect primarily the older, and is characterized by intense and progressive neuronal degeneration following by a severe cognitive decline. The presence of neurofibrillary tangles containing hyperphosphorilated Tau and senile plaques containing the beta amyloid peptide are histopathological hallmarks of AD. Insoluble beta amyloid are less toxic that the oligomers or monomers itself. A²1-42 is the proteolytic cleavage of the amyloid precursor protein (APP). The rule of A²1-42 in a healthy brain is still under investigation and its functions are essential to tissue development and maintenance in the central and peripheral nervous system. It is also required for proper growth cone formation and axon outgrowth, neural differentiation, and synaptic transmission. A²1-42 has both neurotrophic and neurotoxic effect depending on the cellular context. Our group has discovered that neurotocicity of A²1-42 is dependent of cell differentiation using SH-SY5Y cell: It is neurotoxic for differentiated cells and neurotrofic to undifferentiated cell. The intracellular machinery responsible for the apparent "switch" between A²1-42 neurotoxic and neurotrophic effect is not known, and may explain some discrepancies found in the scientific literature regarding the effect of A²1-42 to Alzheimer's disease development. Our laboratory has identity a gene called BAG2 that may explain the dual effect of A²1-42 in SH-SY5Y cell line. The effect of A²1-42 has changed from trophic to toxic in undifferentiated cell overexpressing BAG2, which express low levels of BAG2. However, our group still does not understand if BAG2 expression is necessary for the toxic effect of A²1-42 in differentiated SH-SY5Y cells. In addition to that we show that the NF-kappaB seems to decrease the levels of BAG2 levels, however the genes responsible for it are still unknown. BAG2 physically associates with the several proteins related with TNF complex, including NF-kappaB signaling complex which activate either anti-apoptotic or pro-apoptotic output. This data suggests that BAG2 may influence A²1-42 effect on cell death regarding AD development.In conclusion, the aim of our proposal is to study the role of BAG2 / NF-kappaB interaction and the genes responsible for the anti-apoptotic or pro-apoptotic output in the context of cell differentiation using the SH-SY5Y cells.

Scientific publications

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

DUFNER-ALMEIDA, LUIZ GUSTAVO; DO CARMO, RAMON TORREGLOSA; MASOTTI, CIBELE; HADDAD, LUCIANA AMARAL; KUMAR, D. Understanding human DNA variants affecting pre-mRNA splicing in the NGS era. ADVANCES IN GENETICS, VOL 103, v. 103, p. 52-pg., 2019-01-01. (13/08028-1, 16/09762-9)