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

• Grant number: 15/23426-9
• Support Opportunities: Regular Research Grants
• 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). Ministério da Educação (Brasil). 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)

Scientific publications

(12)

(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)

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, OCT 2018. (13/25503-5, 15/02991-0, 15/23426-9)

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, DEC 2018. (13/25503-5, 15/23426-9, 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, JUL 21 2021. (15/23426-9, 15/25541-0)

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, OCT 20 2019. (14/14661-1, 17/12648-6, 15/23426-9, 16/24773-7, 15/02991-0)

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, FEB 2 2019. (13/25503-5, 15/23426-9, 15/02991-0)

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, MAR 2018. (13/25503-5, 15/02991-0, 15/23426-9)

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, SEP 21 2018. (16/24773-7, 15/02991-0, 14/14661-1, 15/23426-9)

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, JAN 2021. (15/23426-9, 13/25503-5, 15/02991-0)

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, 2018. (15/02991-0, 16/24577-3, 15/23426-9)

CHAVES, RODRIGO S.; KAZI, AMAJAD, I; SILVA, CAROLLINY M.; ALMEIDA, MICHAEL F.; LIMA, RAQUEL S.; CARRETTIERO, DANIEL C.; DEMASI, MARILENE; FERRARI, MERARI F. R.. Presence of insoluble Tau following rotenone exposure ameliorates basic pathways associated with neurodegeneration. IBRO REPORTS, v. 1, p. 14-pg., 2016-12-01. (11/15281-0, 11/00478-2, 15/18961-2, 11/15283-2, 13/08028-1, 15/23426-9)

VIZIN, ROBSON CRISTIANO LILLO; HARRIS, GRANT; KUNSTETTER, ANA CANCADO; ALMEIDA, MARIA CAMILA; CARRETTIERO, DANIEL CARNEIRO; ROMANOVSKY, ANDREJ A.. Isoflurane-Induced Hypothermia Does Not Aggravate Memory Impairment in A Sporadic Alzheimer's Disease Rat Model Produced by Intracerebroventricular Streptozotocin. FASEB JOURNAL, v. 33, p. 2-pg., 2019-04-01. (15/02991-0, 16/01836-3, 15/23426-9)

CARRETTIERO, DANIEL CARNEIRO; FARDIN, NUBIA M.; DO CARMO, RAMON TORREGLOSA; ALMEIDA, MARIA CAMILA. Effect of Beta-amyloid on cell death-related molecules: Is the co-chaperone BAG2 a potential target for Alzheimer's disease?. FASEB JOURNAL, v. 33, p. 2-pg., 2019-04-01. (15/23426-9)