No abstract

5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aβ-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age.Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, TNF-α and IL-6); no changes were found in non-amyloidogenic pathway indicators such as ADAM10.Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a and G9a. Histone deacetylase 2 (Hdac2) or Sirt6., both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.

The amyloid-β protein precursor/presenilin 1 (AβPP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern. AD is a neurodegenerative process that causes severe cognitive impairment; it is characterized by the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau forms and by oxidative and inflammatory processes in brain. Currently, efforts are made to understand biochemical pathways because there is no effective therapy for AD. Resveratrol is a polyphenol that induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of oral resveratrol administration on AβPP/PS1 mice. Long-term resveratrol treatment significantly prevented memory loss as measured by the object recognition test. Moreover, resveratrol reduced the amyloid burden and increased mitochondrial complex IV protein levels in mouse brain. These protective effects of resveratrol were mainly mediated by increased activation of Sirtuin 1 and AMPK pathways in mice. However, an increase has been observed in IL1β and TNF gene expression, indicating that resveratrol promoted changes in inflammatory processes, although no changes were detected in other key actors of the oxidative stress pathway. Taken together, our findings suggest that resveratrol is able to reduce the harmful process that occurs in AβPP/PS1 mouse hippocampus, preventing memory loss.

Resveratrol is a natural compound that mimics the antioxidant and antiaging effects of caloric restriction, mainly mediated through SIRT1, a deacetylase that induces longevity and neuroprotection. We aimed to analyze the effects of resveratrol on the brain status of control non-transgenic (NoTg) and AD transgenic (3xTg-AD) mice to discern the mechanisms involved in a potential inducement of resilience against age-related neurodegeneration and Alzheimer's disease (AD). Mice were fed with a diet supplemented with 100 mg/kg of resveratrol from 2 months of age during 10 months. Resveratrol administration induced complete protection against memory loss and brain pathology in 3xTg-AD mice, and also induced cognitive enhancement in healthy NoTg mice. Resveratrol improved exploration and reduced anxiety in both mouse strains, indicative of well-being. Resveratrol reduced the presence of Aβ and p-tau pathology in the hippocampus of the 3xTg-AD mouse. Proteostasis analysis showed the following in both NoTg and 3xTg-AD mice: (i) increased levels of the amyloid-degrading enzyme neprilysin, (ii) reduction of the amyloidogenic secretase BACE1, and (iii) increase of proteasome protein levels and enhancement of proteasome activity. Resveratrol also increased AMPK protein levels, then upregulating the SIRT1 pathway, as shown by the activation of PGC-1α and CREB in both mice, resulting in further beneficial changes. Our data demonstrated that resveratrol induces cognitive enhancement and neuroprotection against amyloid and tau pathologies. Improvement of proteostasis by resveratrol, in both healthy and AD mice, suggests that it is a mechanism of brain resilience and defense against neurodegeneration caused by the accumulation of aberrant proteins.