Secretases, cathepsins and inflamasomes evaluation for Alzheimer’s Disease: new pathways and treatments

• Grant number: 19/19929-6
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2020
• End date: November 30, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Juliana Mozer Sciani
• Grantee: Juliana Mozer Sciani
• Host Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil
• Associated researchers: Daniel Carvalho Pimenta ; Fernanda Bruschi Marinho Priviero ; Giovanna Barbarini Longato ; Hugo Vigerelli de Barros

Abstract

The Alzheimer´s Disease (AD) is the 7th leading cause of death worldwide, and there is no effective therapy available to cure the disease so far. Current treatment available is based on cholinesterase inhibitors. The common sense is that the secretases activity on APP protein generates ²-amyloid peptides (A²), which aggregate and accumulate in certain parts of the brain, causing mitochondrial and lysosomal dysfunction, inflammation and apoptosis. The secretases inhibitors have been studied as alternative, although have demonstrated high toxicity or lack of efficacy. Nevertheless, these enzymes as still considered good therapeutic targets. The neurons´ defense mechanism, regarding lysosomal cathepsins activity, are controversy. However, it is a consensus that the autophagy and mitochondria are impaired, while the inflammatory mediators are released, and its source can be the cathepsin and inflammasome formation. There is no description of efficient molecules that act on cathepsins or inflammasomes, as well as mitochondria, and in this context, antioxidants have demonstrated efficacy, but still unknown in the clinic. Thus, the better understanding of the disease, in the cellular level, is necessary, besides the search for new molecules for a possible treatment. In this work, new secretases, inflammasome and Reactive Oxygen Species release (ROS) inhibitors will be searched, as well as cathepsins modulators, obtained from marine and amphibians from Brazilian biodiversity. The extracts will be selected and fractionated according to their enzymatic activity on synthetic substrates and active molecules will be tested in A²-treated neurons for evaluation of amyloid plates reduction. Thus, we expect to find a correlation between the enzyme modulation or ROS release and reduction of amyloid plates, being a new alternative for the AD treatment or a tool for a better comprehension of the disease. (AU)

Scientific publications

(6)

(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)

BANAGOURO, KARINE CRISTIE QUAGLIO; VIANA, JEFFERSON; DE LIMA, LEONARDO PEREIRA; COELHO, GUILHERME RABELO; ROCHA, THALITA; GIRARDELLO, RAQUEL; RUSSI, KAROLAYNE LARISSA; KITAHARA, MARCELO V.; SCIANI, JULIANA MOZER. Biochemical and Toxinological Characterization of Venom from Macrorhynchia philippina (Cnidaria, Hydrozoa). BIOMED RESEARCH INTERNATIONAL, v. 2022, p. 10-pg., 2022-05-17. (19/19929-6)

ARRUDA, GIAN LUCAS M.; VIGERELLI, HUGO; BUFALO, MICHELLE C.; LONGATO, GIOVANNA B.; VELOSO, RODINEI V.; ZAMBELLI, VANESSA O.; PICOLO, GISELE; CURY, YARA; MORANDINI, ANDRE C.; MARQUES, ANTONIO CARLOS; et al. Box Jellyfish (Cnidaria, Cubozoa) Extract Increases Neuron's Connection: A Possible Neuroprotector Effect. BIOMED RESEARCH INTERNATIONAL, v. 2021, MAR 5 2021. (15/21007-9, 15/50040-4, 16/06137-6, 19/19929-6, 13/07467-1, 11/50242-5)

MORENO, RAFAELA INDALECIO; ZAMBELLI, VANESSA O.; PICOLO, GISELE; CURY, YARA; MORANDINI, ANDRE C.; MARQUES, ANTONIO CARLOS; SCIANI, JULIANA MOZER. Caspase-1 and Cathepsin B Inhibitors from Marine Invertebrates, Aiming at a Reduction in Neuroinflammation. MARINE DRUGS, v. 20, n. 10, p. 12-pg., 2022-10-01. (19/19929-6, 13/07467-1)

BOLDIN, RENATA; ZYCHAR, BIANCA CESTARI; GONCALVES, LUIS ROBERTO C.; SCIANI, JULIANA MOZER. Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1. FRONTIERS IN PHARMACOLOGY, v. 14, p. 11-pg., 2023-06-16. (19/19929-6)

AMANDA GOMES DA SILVA; MARIANA DA MATA ALVES; ADMILSON APARECIDO DA CUNHA; GIOVANNA ARRUDA CAIRES; IRINA KERKIS; HUGO VIGERELLI; JULIANA MOZER SCIANI. Echinometra lucunter molecules reduce Aβ42-induced neurotoxicity in SH-SY5Y neuron-like cells: effects on disaggregation and oxidative stress. Journal of Venomous Animals and Toxins including Tropical Diseases, v. 29, 2023-12-01. (19/19929-6)

COELHO, GUILHERME RABELO; DA SILVA, DAIANE LAISE; BERALDO-NETO, EMIDIO; VIGERELLI, HUGO; DE OLIVEIRA, LAUDICEIA ALVES; SCIANI, JULIANA MOZER; PIMENTA, DANIEL CARVALHO. Neglected Venomous Animals and Toxins: Underrated Biotechnological Tools in Drug Development. TOXINS, v. 13, n. 12, p. 23-pg., 2021-12-01. (19/19929-6)