Role of kinin-B2 receptor in pathogenesis and progression of familial Alzheimer's Disease: from neurogenesis and immune response to cognition

• Grant number: 15/19478-3
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2016
• Effective date (End): December 18, 2019
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Micheli Mainardi Pillat
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases, AP.TEM

Abstract

Alzheimer's disease (AD) is a progressive degenerative disorder that affects more than 35 millions of people throughout the world and still has no therapy able to stop its course or even prevent its instauration. Abnormal neurogenesis and neuroinflammation are processes inherent to pathogenesis of AD, and therefore signs that promote these processes can act as initial deleterious triggers. In this context, recent data show that the kinin system is stimulated by the pathologic ²-amyloid (²A) in AD patients. The effects of this system are primarily mediated by bradykinin (BK) and its kinin-B2 receptor (B2R), and comprehend the direct action on neural stem cells inducing neurogenesis, growth of neurites, permeabilization of the blood-brain barrier, synthesis of IL12 (that results in polarization of lymphocytes to the Th1 cytokine profile) and the strong mediation of inflammation that for its turn can also affect neurogenesis. However, the role of BK/B2R in the processes inherent to AD pathogenesis (neurogenesis and inflammation) and its progression is unknown. This project proposes to elucidate this role by using transgenic double mice as model of the familial AD, both expressing or not expressing B2R (APPswe/PSldE9+/-B2R-/- and APPswe/PSldE9+/-B2R-/-). For identification of possible downstream mechanisms of BK mediated by inflammation and cellular immune response APPswe/PSldE9 mice treated with minocycline and knockout animals for IL-12, respectively, will also be used. Half of these animals will be treated with a stable agonist of the B2R (lysyl-BK). These study groups will be evaluated for neural differentiation, including proliferation and neurogenesis of neural stem cells (NSCs) as well as the dendritic survival and complexity of young neurons in the hippocampus of mice of 2 and 6 months of life. The NSCs of these animals will also be differentiated and treated in vitro to evidence or to exclude any effects on the inflammatory niche. At the same time, patterns of inflammation and cellular immune response in the hippocampus will be determined, such as the levels of the main proinflammatory cytokines, the frequency of activated microglia and T cells. Finally, effects of BK/B2R and subsequent possible mechanisms downstream on AD pathogenesis and progression through the detected concentration of ²A, frequency of ²A platelets and cognitive deficits, will be determined. (AU)

Scientific publications

(11)

(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)

CORREA-VELLOSO, JULIANA C.; GONCALVES, MARIA C. B.; NAALDIJK, YAHAIRA; OLIVEIRA-GIACOMELLI, AGATHA; PILLAT, MICHELI M.; ULRICH, HENNING. Pathophysiology in the comorbidity of Bipolar Disorder and Alzheimer's Disease: pharmacological and stem cell approaches. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 80, n. A, p. 34-53, JAN 3 2018. (15/14343-2, 15/19478-3, 12/50880-4)

REICHERT, KARINE P.; PILLAT, MICHELI M.; SCHETINGER, MARIA ROSA C.; BOTTARI, NATHIELI B.; PALMA, V, TAIS; ASSMANN, CHARLES E.; GUTIERRES, JESSIE M.; ULRICH, HENNING; ANDRADE, CINTHIA M.; EXLEY, CHRISTOPHER; et al. Aluminum-induced alterations of purinergic signalling in embryonic neural progenitor cells. Chemosphere, v. 251, JUL 2020. (18/07366-4, 15/19478-3)

BOTTARI, NATHIELI B.; SCHETINGER, MARIA ROSA C.; PILLAT, MICHELI M.; PALMA, THAIS V.; ULRICH, HENNING; ALVES, MARIANA S.; MORSCH, VERA M.; MELAZZO, CINTHIA; DE BARROS, LUIZ DANIEL; GARCIA, JOAO LUIS; et al. Resveratrol as a Therapy to Restore Neurogliogenesis of Neural Progenitor Cells Infected by Toxoplasma gondii. Molecular Neurobiology, v. 56, n. 4, p. 2328-2338, APR 2019. (12/50880-4, 15/19478-3)

SOBROZA, ANDERSON O.; PILLAT, MICHELI M.; DORNELES, GUILHERME L.; MACHADO, MARCIA S. N.; SILVA, CASSIA B.; PETRY, LETICIA; SCHAFER, ANDRESSA; FRANCA, RAQUELI T.; DE ANDRADE, CINTHIA M.; ANTONIAZZI, ALFREDO Q.; et al. Anti-erythrocyte IgG in hamsters with acute experimental infection by Leptospira interrogans serovar Canicola. Microbial Pathogenesis, v. 110, p. 450-456, SEP 2017. (15/19478-3)

VIEIRA, JULIANO MARCHI; GUTIERRES, JESSIE MARTINS; CARVALHO, FABIANO BARBOSA; STEFANELLO, NAIARA; OLIVEIRA, LIZIELLE; CARDOSO, ANDREIA MACHADO; MORSCH, VERA MARIA; PILLAT, MICHELI MAINARDI; ULRICH, HENNING; FRESCURA DUARTE, MARTA MEDEIROS; et al. Caffeine and high intensity exercise: Impact on purinergic and cholinergic signalling in lymphocytes and on cytokine levels. BIOMEDICINE & PHARMACOTHERAPY, v. 108, p. 1731-1738, DEC 2018. (12/50880-4, 15/19478-3)

FRUHAUF-PEREZ, PAMELLA K.; TEMP, FERNANDA R.; PILLAT, MICHELI M.; SIGNOR, CRISTIANE; WENDEL, ARITHANE LORENA; ULRICH, HENNING; MELLO, CARLOS F.; RUBIN, MARIBEL A.. Spermine protects from LPS-induced memory deficit via BDNF and TrkB activation. NEUROBIOLOGY OF LEARNING AND MEMORY, v. 149, p. 135-143, MAR 2018. (15/19478-3)

REICHERT, KARINE P.; SCHETINGER, MARIA ROSA C.; PILLAT, MICHELI M.; BOTTARI, NATHIELI B.; PALMA, TAIS V.; GUTIERRES, JESSIE M.; ULRICH, HENNING; ANDRADE, CINTHIA M.; EXLEY, CHRISTOPHER; MORSCH, VERA M. M.. Aluminum affects neural phenotype determination of embryonic neural progenitor cells. ARCHIVES OF TOXICOLOGY, v. 93, n. 9, p. 2515-2524, SEP 2019. (12/50880-4, 15/19478-3)

BOTTARI, NATHIELI B.; PILLAT, MICHELI M.; SCHETINGER, MARIA R. C.; REICHERT, KARINE P.; MACHADO, VANESSA; ASSMANN, CHARLES E.; ULRICH, HENNING; DUTRA, ANIELEN; MORSCH, VERA M.; VIDAL, TAIS; et al. Resveratrol-mediated reversal of changes in purinergic signaling and immune response induced by Toxoplasma gondii infection of neural progenitor cells. PURINERGIC SIGNALLING, v. 15, n. 1, p. 77-84, MAR 2019. (12/50880-4, 15/19478-3)

TEMP, FERNANDA ROSSATTO; MARAFIGA, JOSEANE RIGHES; MILANESI, LAURA HAUTRIVE; DUARTE, THIAGO; RAMBO, LEONARDO MAGNO; PILLAT, MICHELI MAINARDI; MELLO, CARLOS FERNANDO. Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazolinduced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice. European Journal of Pharmacology, v. 810, p. 15-25, SEP 5 2017. (15/19478-3)

PINTO FILHO, SAULO T. L.; PILLAT, MICHELI M.; ROSA, MATHEUS P.; DALMOLIN, FABIOLA; ULRICH, HENNING; PIPPI, NEY L.. Padrão de expressão de proteínas específicas das células-tronco mesenquimais derivadas de tecido adiposo: possível agente imunossupressor em aloenxerto parcial para restauração de vesícula urinária de coelhos. Pesquisa Veterinária Brasileira, v. 38, n. 12, p. 2183-2189, DEC 2018. (15/19478-3, 12/50880-4)

FRANCA, RAQUELI TERESINHA; PILLAT, MICHELI MAINARDI; DA SILVA, CASSIA BAGOLIN; SCHAFER, ANDRESSA SALVADORI; DORNELLES, GUILHERME LOPES; COSTA, MARCIO MACHADO; CHAVES, RAFAEL OLIVEIRA; DE ANDRADE, CINTHIA MELAZZO; ERHARDT, MAGNOLIA MARTINS; ANTOZIAZZI, ALFREDO QUITES; et al. Surface immunoglobulins of erythrocytes and platelets in dogs naturally infected by Rangelia vitalii. Microbial Pathogenesis, v. 121, p. 245-251, AUG 2018. (12/50880-4, 15/19478-3)