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 inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with two compounds that have entered clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's Disease (AD). Of interest, we have found that sEH is upregulated in brains from AD patients. We have evaluated the cognitive impairment and the pathological hallmarks in two models of age-related cognitive decline and AD using three structurally different and potent sEH inhibitors as chemical probes. Our findings supported our expectations on the beneficial effects of central sEH inhibition, regarding of reducing cognitive impairment, tau hyperphosphorylation pathology and the number of amyloid plaques. Interestingly, our results suggest that reduction of inflammation in the brain is a relevant therapeutic strategy for all stages of AD.

Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here, we determined the effect of age in SAMP8, and compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of ALDH2, IL-6, HMOX1, COX2, CXCL10, iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and BACE1, and reduced ADAM10 expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration.

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.

Oxidative stress is a major pathogenic factor in Alzheimer's disease, but it should not be tackled alone rather together with other key targets to derive effective treatments. The combination of the scaffold of the polar antioxidant lead 7-methoxy-2,2dimethylchroman-6-ol (CR-6) with that of the lipophilic cholinesterase inhibitor 6-chlorotacrine results in compounds with favorable brain permeability and multiple activities in vitro (acetylcholinesterase, butyrylcholinesterase, β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1), and Aβ42 and tau aggregation inhibition). In in vivo studies on wild-type and APP/ presenilin 1 (PS1) mice, two selected compounds were well tolerated and led to positive trends, albeit statistically nonsignificant in some cases, on memory performance, amyloid pathology (reduced amyloid burden and potentiated non-amyloidogenic APP processing), and oxidative stress (reduced cortical oxidized proteins and increased antioxidant enzymes superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1 (GPX1), and heme oxygenase 1 (Hmox1) and transcription factor nuclear factorerythroid 2-related factor 2 (Nrf2)). These compounds emerge as interesting brain-permeable multitarget compounds, with a potential as anti-Alzheimer agents beyond that of the original lead CR-6.