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Study of cannabinoid compounds modulation in the autophagy mediated by TFEB in a cellular Tauophathy model

Grant number: 18/06260-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2019
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Gustavo José da Silva Pereira
Grantee:Talita Aparecida de Moraes Vrechi
Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil
Associated research grant:16/20796-2 - Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models, AP.JP

Abstract

Alzheimer's Disease (AD) is one of the most studied neurodegenerative diseases, being a common cause of Dementia in the elderly. The hyperphosphorylated Tau protein is the neuron pathological hallmark for diseases called Tauopathies, such as AD, and consequently, may lead to cell death. Autophagy is crucial for neuronal homeostasis, since autophagic dysfunctions are related to abnormal accumulation of toxic aggregates. Hence, the autophagy modulation has been postulated as a possible therapeutic target, in which the Transcription Factor EB (TFEB) is an important and recent activator of autophagy. Recent evidences indicated that cannabinoid compounds play a potential neuroprotective role in several neurodegenerative models, but the autophagic pathways mediated by these compounds is still unknown. In this present project, we will investigate the possible neuroprotective role for cannabinoids-mediated autophagy through TFEB pathway in an in vitro neuronal model of tauopathy. For this purpose, an SH-SY5Y neuronal line, overexpressing human Tau protein, will be characterized and then treated with cannabinoid compounds. Experiments, such as Western Blotting or real-time PCR, will be performed to evaluate the pathways related to autophagic flux, TFEB signaling and Tau protein degradation. Using confocal microscopy, we will evaluate the morphology and functionality of autophagossomes and lysosomes. Thus, this study highlights the importance of cannabinoids and the autophagy induction, and its contribution to a potential development of therarapeutic targets on Tauopathies. (AU)