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

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

doi:10.1016/j.ibror.2016.09.001

Rodrigo S Chaves, Amajad I Kazi + Show 6 more

Open Access

https://doi.org/10.1016/j.ibror.2016.09.001

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Abstract

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 (Aβ). 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.

Highlights

Neurodegeneration is often associated with the presence of extra and intracellular protein aggregates distributed throughout the central nervous system (CNS)
Soluble levels of hyperphosphorylated Tau normalized to total Tau levels in hippocampal cultures revealed an increase by 60% and 35%, 48 h after exposure to 0.3 nM and 0.5 nM of rotenone, respectively, as compared to DMSO (Fig. 1A)
Immunocytochemical labeling of hippocampal cultures showed that immunoreactivity for Tau hyperphosphorylated is mainly localized in the neurites and its raises as rotenone concentration increase (Fig. 1C)

Summary

Introduction

Neurodegeneration is often associated with the presence of extra and intracellular protein aggregates distributed throughout the central nervous system (CNS). Several neurodegenerative disorders, including Alzheimer's disease (AD) and frontotemporal dementia, are characterized by the presence of intracellular inclusions of neurofibrillary tangles (NTFs) and paired helical filaments (PHFs). These inclusions are mainly composed of hyperphosphorylated Tau (Ross and Poirier, 2005; Frost et al, 2015). The presence of intracellular inclusions of Tau is believed to disrupt neuron physiology, through alterations in microtubule dynamics (Kuret et al, 2005), axonal transport (Cuchillo-Ibanez et al, 2008; Shahpasand et al, 2012; Smith and Bennett, 1997), synaptic function (Scheff et al, 2013) and loss of redox homeostasis (Melo et al, 2011). Proteasome and autophagy pathways, mechanisms involved in clearing hyperphosphorylated Tau/Tau aggregates, are suggested to be dysregulated during the etiology of tauopathies (Huang and Figueiredo-Pereira, 2010; Ben-Gedalya and Cohen, 2012)

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