Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis

• Grant number: 14/25681-3
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: August 01, 2015
• End date: April 30, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Adriano Silva Sebollela
• Grantee: Adriano Silva Sebollela
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 19/23429-9 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis, BP.TT; 19/22299-4 - Preparation, maintenance and quality control of slice cultures from adult human brains, BP.TT; 18/25124-8 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis, BP.TT; 18/24411-3 - Molecular basis of the toxicity of protein oligomers associated to brain amyloidosis, BP.TT; 15/17353-9 - Molecular basis of protein oligomers toxicity associated with nervous system amyloidosis, BP.IC

Abstract

Toxic protein oligomers are believed to be the main culprit for the synaptic loss and cognitive decline in proteinopathies afflicting the central nervous system (CNS), as Alzheimer's, Parkinson, and prionoses. As a result, the interaction between oligomers and neurons is now seen as a preferential target for the development of novel therapeutic strategies against these neuropathologies. On the other hand, detailed structure of these toxic species is still unknown, as the molecular events underlying oligomer-elicited neurotoxicity. Here our main goal is to understand the molecular and cellular mechanism linked to the neurotoxicity of protein oligomers associated to diseases. The experimental approach is centered on the use of novel human single chain antibodies able to distinguish toxic oligomers from their non-toxic assemblies’ counterparts. The work will focus on determining the neuroprotection of anti-oligomer scFv's exhibiting distinct specificities for each oligomeric assembly on both in vitro and in vivo models of CNS. Through this approach we hope to significantly contribute to the development of reagents with therapeutic and diagnostic potential against these devastating and still cureless diseases. (AU)

Scientific publications

(7)

(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)

VASCONCELOS, ISRAEL C.; CAMPOS, RAQUEL M.; SCHWAEMMLE, HANNA K.; MASSON, ANA P.; FERRARI, GUSTAVO D.; ALBERICI, LUCIANE C.; FAC, VITOR M.; GARCIA-CAIRASCO, NORBERTO; SEBOLLELA, ADRIANO. Research Article A freeze-and-thaw-induced fragment of the microtubule-associated protein tau in rat brain extracts: implications for the biochemical assessment of neurotoxicity. BIOSCIENCE REPORTS, v. 41, n. 3, MAR 24 2021. (14/25681-3)

NOGUEIRA, GIOVANNA O. O.; GARCEZ, PATRICIA P. P.; BARDY, CEDRIC; CUNNINGHAM, MARK O. O.; SEBOLLELA, ADRIANO. Modeling the Human Brain With ex vivo Slices and in vitro Organoids for Translational Neuroscience. FRONTIERS IN NEUROSCIENCE, v. 16, p. 6-pg., 2022-02-24. (14/25681-3)

SELLES, MARIA CLARA; FORTUNA, JULIANA T. S.; CERCATO, MAGALI C.; SANTOS, LUIS EDUARDO; DOMETT, LUCIANA; BITENCOURT, ANDRE L. B.; CARRARO, MARIANE FAVERO; SOUZA, AMANDA S.; JANICKOVA, HELENA; AZEVEDO, CAROLINE VIEIRA; et al. AAV-mediated neuronal expression of an scFv antibody selective for Af3 oligomers protects synapses and rescues memory in Alzheimer models. MOLECULAR THERAPY, v. 31, n. 2, p. 11-pg., 2023-02-01. (14/25681-3)

ALMEIDA, GLAUCIA M.; SOUZA, JULIANO P.; MENDES, NIELE D.; PONTELLI, MARJORIE C.; PINHEIRO, NATHALIA R.; NOGUEIRA, GIOVANNA O.; CARDOSO, RICARDO S.; PAIVA, ISADORA M.; FERRARI, GUSTAVO D.; VERAS, FLAVIO P.; et al. Neural Infection by Oropouche Virus in Adult Human Brain Slices Induces an Inflammatory and Toxic Response. FRONTIERS IN NEUROSCIENCE, v. 15, NOV 23 2021. (14/02438-6, 18/06614-4, 14/25681-3)

BITENCOURT, ANDRE L. B.; CAMPOS, RAQUEL M.; CLINE, ERIKA N.; KLEIN, WILLIAM L.; SEBOLLELA, ADRIANO. Antibody Fragments as Tools for Elucidating Structure-Toxicity Relationships and for Diagnostic/Therapeutic Targeting of Neurotoxic Amyloid Oligomers. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 23, DEC 2020. (14/25681-3)

SEBOLLELA, ADRIANO; CLINE, ERIKA N.; POPOVA, IZOLDA; LUO, KEVIN; SUN, XIAOXIA; AHN, JAY; BARCELOS, MILENA A.; BEZERRA, VANESSA N.; LYRA E SILVA, NATALIA M.; PATEL, JASON; et al. A human scFv antibody that targets and neutralizes high molecular weight pathogenic amyloid-beta oligomers. Journal of Neurochemistry, v. 142, n. 6, p. 934-947, SEP 2017. (14/25681-3)

DE ALMEIDA, VALERIA; MENDES, NIELE DIAS; ZUCCOLI, GIULIANA S.; REIS-DE-OLIVEIRA, GUILHERME; ALMEIDA, GLAUCIA M.; PODOLSKY-GONDIM, GUILHERME GOZZOLI; NEDER, LUCIANO; MARTINS-DE-SOUZA, DANIEL; SEBOLLELA, ADRIANO. NMDA glutamate receptor antagonist MK-801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine. Journal of Neurochemistry, v. 168, n. 3, p. 13-pg., 2024-02-08. (21/12263-2, 17/18242-1, 18/06614-4, 17/25588-1, 14/25681-3)