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Neutralizing beta-amyloid peptide oligomers neurotoxicity by the controlled neuronal expression of the conformational single chain antibody NUsc1

Grant number: 18/10721-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2019
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Adriano Silva Sebollela
Grantee:Nathalia Reges Pinheiro
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Soluble oligomers of the Abeta peptide (AbetaOs) are the major neurotoxins related to cognitive deficits in Alzheimer's disease (AD). With increasing life expectancy of the population, and absence of efficient pre-mortem diagnostic and treatment methods for AD, conformational antibodies specific for AbetaOs are seen as a promising therapeutic strategy. However, clinical trials with anti-Abeta IgG's resulted in inflammatory side effects mediated by the interaction of the non-variable Fc portion with microglial Fcgama receptors, resulting in rupture of the blood-brain barrier. Then, artificial conformational antibodies of the scFv type, lacking the Fc portion, were screened against AbetaOs. Among them, NUsc1, capable of neutralizing the neurotoxicity of relevant AbetaO species in AD pathogenesis in neuronal primary culture, appears prominently. In this project, we intend to establish the therapeutic potential of NUsc1 for AD, assessing whether this antibody is neuroprotective against AbetaOs when expressed constitutively and secreted by neuronal cells. In addition, we will analyze the possibility of regulation of the NUsc1 expression by an exogenously controlled on/ off system. We will check the safety of its therapeutic use when analyzing whether NUsc1 generates proinflammatory adverse effects mediated by microglial activation, and whether the resulting NUsc1-AbetaO complex is metabolized via microglial phagocytosis, a possible mechanism to eliminate this complex from the CNS. Finally, we hope to contribute to the evaluation of the use of single-chain antibodies as immunotherapeutics in AD, and to generate a vector for constitutive and controlled expression in eukaryotic cells of scFv's candidates to treat neuropathologies.