Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

Tom L Broderick,Miranda Anderson,Thangiah Geetha,Layla Al-Nakkash,Yuxian Zhang,Suhail Rasool,Jeganathan Ramesh Babu,Rongzi Li,Jeffrey H Plochocki

doi:10.3390/ijms21197337

Abstract

To date, there is no cure or effective treatment for Alzheimer’s disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Highlights

Alzheimer’s disease (AD) is the most prevalent form of dementia and patients with this neurodegenerative disease exhibit cognitive impairment, memory loss, and behavioral manifestations [1]
In terms of the effects of treatment, our data show that: (1) exercise training (ET) decreased the accumulation of Aβ oligomers and markers of autophagy, (2) Resv reduced markers related to inflammation, toxic species of Aβ, apoptosis, autophagy, ubiquitination and endolysosomal degradation, (3) Resv increased the expression of neurotrophins and SIRT1, and (4) combined ET and Resv was as effective and beneficial as Resv treatment alone except for an increase in synaptophysin and PSD95 synthesis
We are the first to document the effects of ET, Resv treatment, and combination treatment on markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection as well as conformational toxic species of Aβ in the brain of the 3xTg mouse model of AD

Summary

Introduction

Alzheimer’s disease (AD) is the most prevalent form of dementia and patients with this neurodegenerative disease exhibit cognitive impairment, memory loss, and behavioral manifestations [1]. There is currently a substantial number of investigations aimed at understanding the role of folding of aggregated Aβ oligomers, which form prior to the development of plaques [6,7,8]. It has been well-established that aggregated Aβ, in oligomer conformation, contributes to mislocalization and hyperphosphorylation of tau [9,10,11,12,13]. It has been observed that intraneuronal Aβ accumulates in early events of AD, which can be detected with M78 antibodies but not by regular Aβ antibodies, including 4G8 and 6E10 [14]

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