Presence of insoluble Tau following rotenone exposure ameliorates basic pathways associated with neurodegeneration

Autor(es)

Chaves, Rodrigo S. ; Kazi, Amajad, I ; Silva, Carolliny M. ; Almeida, Michael F. ; Lima, Raquel S. ; Carrettiero, Daniel C. ; Demasi, Marilene ; Ferrari, Merari F. R.

• Tipo de documento: Artigo Científico
• Fonte: IBRO REPORTS; v. 1, p. 14-pg., 2016-12-01.

Resumo

Protein aggregation is an important feature of neurodegenerative disorders. In Alzheimer's disease (AD) protein aggregates are composed of hyperphosphorylated Tau and amyloid beta peptide (Ab). Despite the involvement and identification of the molecular composition of these aggregates, their role in AD pathophysiology is not fully understood. However, depositions of these insoluble aggregates are typically reported as pathogenic and toxic for cell homeostasis. New evidences suggest that the deposition of these aggregates is a protective mechanism that preserves cell from toxic insults associated with the early stages of neurodegenerative diseases. To better understand the biological role of the protein aggregation with regard its effects in cellular homeostasis, the present study investigated the role of insoluble Tau and Tau aggregates on crucial cellular parameters such as redox homeostasis, proteasome activity and autophagy in hippocampal cell cultures and hippocampus of aged Lewis rats using a rotenone-induced aggregation model. Neurons were exposed to rotenone in different concentrations and exposure times aiming to determine the interval required for Tau aggregation. Our experimental design allowed us to demonstrate that rotenone exposure induces Tau hyperphosphorylation and aggregation in a concentration and time-dependent manner. Oxidative stress triggered by rotenone exposure was observed with the absence of Tau aggregates and was reduced or absent when Tau aggregates were present. This reduction of oxidative stress along with the presence of insoluble Tau was independent of alterations in antioxidant enzymes activities or cell death. In addition, rotenone induced oxidative stress was mainly associated with decrease in proteasome activity and autophagy flux. Conversely, when insoluble Tau appeared, autophagy turns to be overactivated while proteasome activity remained low. Our studies significantly advance the understanding that Tau aggregation might exert protective cellular effects, at least briefly, when neurons are facing neurodegeneration stimulus. We believe that our data add more complexity for the understanding of protein aggregation role in AD etiology. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of International Brain Research Organization. (AU)

• Processo FAPESP: 11/15281-0 - Efeitos do exercício físico moderado sobre o tráfego de neurotrofinas e seus receptores no sistema nervoso central de ratos idosos
• Beneficiário: Michael Fernandes de Almeida
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 11/00478-2 - Influência do cálcio e das proteínas MIRO na mobilidade mitocondrial anteriormente e durante a agregação de proteínas envolvidas em neurodegeneração
• Beneficiário: Rodrigo dos Santos Chaves
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 15/18961-2 - Estudo da autofagia como mecanismo para o desencadeamento de doenças neurodegenerativas
• Beneficiário: Merari de Fátima Ramires Ferrari
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/15283-2 - Autofagocitose e estresse oxidativo no sistema nervoso central de ratos idosos submetidos ao exercício físico moderado
• Beneficiário: Carolliny Moura da Silva
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/23426-9 - Beta amiloide na patologia de Alzheimer: morte ou sobrevivência? Envolvimento da via NF-kappaB e BAG2
• Beneficiário: Daniel Carneiro Carrettiero
• Modalidade de apoio: Auxílio à Pesquisa - Regular