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Study of the cell survival modulation by B2 receptor for bradykinin and its impact on neuroinflamation in organotypic hippocampal culture of transgenic mice for Alzheimer's Disease

Grant number: 17/21655-6
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2018
Effective date (End): August 31, 2021
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Hudson de Sousa Buck
Grantee:Mariana Toricelli Pinto
Home Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil

Abstract

The kallikrein-kinin system has been associated with inflammation and immunogenic responses in the nervous and peripheral systems by activation of two receptors, B1 and B2. The B1 receptor is absent or poorly expressed under physiological conditions, its overexpression occurs when a tissue injury occurs or in the cytokines presence.. The B2 receptor has constitutive expression and mediates most biological effects of kinins. Alzheimer's disease is characterized by cognitive decline, presence amyloid beta peptide aggregates (A2), and neurofibrillary tangles formed by hyperphosphorylation of Tau protein. Recently the Dr Hudson Buck group observed an bradykinin (BK) increase in cerebrospinal fluid and increased binding density for B1 and B2 receptors in memory-related areas after chronic amyloid beta infusion in rats, in which it was monitored memory impairment and neuronal loss. Memory impairment was also observed in C57BL/6 mice submitted to chronic infusion of beta amyloid (A²), whereas C57BL/6 mice with gene deletion for B1 receptor (KOB1) or B2 receptor (KOB2) presented different responses . In the KOB2 mice chronic amyloid beta infusion accelerated the cognitive deficit, whereas in the KOB1 animals no changes were observed. Increased synapses were also observed in KOB1 animals infused with beta amyloid and amyloid beta deposition in KOB2 animals. Memory preservation observed in KOB1 animals receiving beta amyloid may be due to increased B2 receptor density and increased synapses, thus suggesting a neuroprotective role of the B2 receptor. In addition, the increase of amyloid beta plaques in KOB2 animals reinforces the hypothesis of the B2 receptor neuroprotective role and that it may be involved in the in vivo degradation of A².Therefore, the objective of this work is to evaluate the participation of the kinin B1 and B2 receptors in Alzheimer's disease using organotypic hippocampal culture of transgenic mice that show overexpression of beta amyloid precursor protein (APP) and also in KOB1 and KOB2 animals. The slices will be treated with agonist and selective antagonist for B2 and antagonist for B1, all resistant to degradation. Neuroinflammatory markers, neural and synaptic plasticity, cellular and subcellular colocalization of B1 and B2 receptors will also be evaluated. These data will contribute to a better pharmacological and neuroanatomical understanding of Alzheimer's disease as well as the role of the cinine B1 and B2 receptors.

Scientific publications
(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)
TORICELLI, MARIANA; PEREIRA, ARTHUR ANTONIO RUIZ; SOUZA ABRAO, GUILHERME; MALERBA, HELENA NASCIMENTO; MAIA, JULIA; BUCK, HUDSON SOUSA; VIEL, TANIA ARAUJO. Mechanisms of neuroplasticity and brain degeneration: strategies for protection during the aging process. NEURAL REGENERATION RESEARCH, v. 16, n. 1, p. 58-67, JAN 2021. Web of Science Citations: 0.
TORICELLI, MARIANA; EVANGELISTA, SEBASTIANA RIBEIRO; BUCK, HUDSON SOUSA; VIEL, TANIA ARAUJO. Microdose Lithium Treatment Reduced Inflammatory Factors and Neurodegeneration in Organotypic Hippocampal Culture of Old SAMP-8 Mice. Cellular and Molecular Neurobiology, JUL 2020. Web of Science Citations: 0.
TORICELLI, MARIANA; EVANGELISTA, SEBASTIANA RIBEIRO; OLIVEIRA, LARISSA ROLIM; VIEL, TANIA ARAUJO; BUCK, HUDSON SOUSA. Neuroprotective Effects of Kinin B2 Receptor in Organotypic Hippocampal Cultures of Middle-Aged Mice. FRONTIERS IN AGING NEUROSCIENCE, v. 11, JUL 12 2019. Web of Science Citations: 0.

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