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Beta-amyloid in Alzheimer's Disease: death or survival? Involvement of NF-kappaB and BAG2


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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Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MOREIRA-SILVA, DANIEL; CARRETTIERO, DANIEL C.; OLIVEIRA, ADRIELE S. A.; RODRIGUES, SAMANTA; DOS SANTOS-LOPES, JOYCE; CANAS, PAULA M.; CUNHA, RODRIGO A.; ALMEIDA, MARIA C.; FERREIRA, TATIANA L.. Anandamide Effects in a Streptozotocin-Induced Alzheimer's Disease-Like Sporadic Dementia in Rats. FRONTIERS IN NEUROSCIENCE, v. 12, . (16/24773-7, 15/02991-0, 15/23426-9, 14/14661-1)
LILLO VIZIN, ROBSON CRISTIANO; CARRETTIERO, DANIEL CARNEIRO; ISHIKAWA, DEBORA T.; CRUZ-NETO, ARIOVALDO P.; ALMEIDA, MARIA CAMILA. Ruthenium red attenuates brown adipose tissue thermogenesis in rats. Journal of Thermal Biology, v. 95, . (15/23426-9, 13/25503-5, 15/02991-0)
DA COSTA, RENATA T.; DOS SANTOS, MARCELLA B.; SILVA, IZABEL C. S.; DE ALMEIDA, RAQUEL P.; TERUEL, MARCELA S.; CARRETTIERO, DANIEL C.; RIBEIRO, CESAR A. J.. Methylmalonic Acid Compromises Respiration and Reduces the Expression of Differentiation Markers of SH-SY5Y Human Neuroblastoma Cells. ACS Chemical Neuroscience, v. 12, n. 14, p. 2608-2618, . (15/23426-9, 15/25541-0)
LILLO VIZIN, ROBSON CRISTIANO; MOTZKO-SOARES, ANNA CAROLINA P.; ARMENTANO, GIOVANA MARCHINI; ISHIKAWA, DEBORA T.; CRUZ-NETO, ARIOVALDO P.; CARRETTIERO, DANIEL CARNEIRO; ALMEIDA, MARIA CAMILA. Short-term menthol treatment promotes persistent thermogenesis without induction of compensatory food consumption in Wistar rats: implications for obesity control. Journal of Applied Physiology, v. 124, n. 3, p. 672-683, . (15/02991-0, 15/23426-9, 13/25503-5)
VICENTE, MARIANE C.; ALMEIDA, MARIA C.; BICEGO, KENIA C.; CARRETTIERO, DANIEL C.; GARGAGLIONI, LUCIANE H.. Hypercapnic and Hypoxic Respiratory Response During Wakefulness and Sleep in a Streptozotocin Model of Alzheimer's Disease in Rats. JOURNAL OF ALZHEIMER'S DISEASE, v. 65, n. 4, p. 1159-1174, . (15/02991-0, 16/24577-3, 15/23426-9)
ISHIKAWA, DEBORA T.; LILLO VIZIN, ROBSON CRISTIANO; DE SOUZA, CRISTIANE OLIVEIRA; CARRETTIERO, DANIEL CARNEIRO; ROMANOVSKY, ANDREJ A.; ALMEIDA, MARIA CAMILA. Camphor, Applied Epidermally to the Back, Causes Snout- and Chest-Grooming in Rats: A Response Mediated by Cutaneous TRP Channels. PHARMACEUTICALS, v. 12, n. 1, . (13/25503-5, 15/23426-9, 15/02991-0)
MOREIRA-SILVA, DANIEL; VIZIN, ROBSON C. L.; MARTINS, TALITA M. S.; FERREIRA, TATIANA L.; ALMEIDA, MARIA C.; CARRETTIERO, DANIEL C.. Intracerebral Injection of Streptozotocin to Model Alzheimer Disease in Rats. BIO-PROTOCOL, v. 9, n. 20, . (14/14661-1, 17/12648-6, 15/23426-9, 16/24773-7, 15/02991-0)
MELO, C.; VIZIN, R. C. L.; SILVA, N. U.; ISHIKAWA, D. T.; ECHEVERRY, M. B.; CARRETTIERO, D. C.; ALMEIDA, M. C.. Early maternal separation promotes alterations in the thermoregulatory profile of adult Wistar rats. Journal of Thermal Biology, v. 78, p. 151-160, . (13/25503-5, 15/23426-9, 15/02991-0)
MOTZKO-SOARES, A. C. P.; VIZIN, R. C. L.; MARTINS, T. M. S.; HUNGARO, A. R. O.; SATO, J. R.; ALMEIDA, M. C.; CARRETTIERO, D. C.. Thermoregulatory profile of neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular streptozotocin in rats. ACTA PHYSIOLOGICA, v. 224, n. 2, . (15/02991-0, 15/23426-9, 13/25503-5)

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