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: 19/03486-8
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2019
• End date: March 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Hudson de Sousa Buck
• Grantee: Hudson de Sousa Buck
• Host Institution: Escola de Artes, Ciências e Humanidades (EACH). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Tânia Araújo Viel

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 during tissue injury or in the presence of cytokines. The B2 receptor is constitutive and mediates most biological effects of kinins. Alzheimer's disease is characterized by cognitive decline, presence of amyloid beta peptide aggregates (AB), and neurofibrillary tangles formed by hyperphosphorylation of Tau protein. We observed a bradykinin (BK) increase in cerebrospinal fluid and increased binding density for B1 and B2 receptors in memory-related areas after chronic infusion of amyloid beta peptide in rats, followed by 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. (AU)

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)

VIEL, TANIA; CHINTA, SHANKAR; RANE, ANAND; CHAMOLI, MANISH; BUCK, HUDSON; ANDERSEN, JULIE. Microdose lithium reduces cellular senescence in human astrocytes - a potential pharmacotherapy for COVID-19?. AGING-US, v. 12, n. 11, p. 10035-10040, JUN 15 2020. (18/05288-6, 19/03486-8)