Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer's Disease Neurodegeneration.

Modulation of Alzheimer's disease (AD) risk begins early in life. During embryo development and postnatal maturation, the brain receives maternal physiological influences and establishes epigenetic patterns that build its level of resilience to late-life diseases. The soluble epoxide hydrolase inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl] urea (TPPU), reported as ant-inflammatory and neuroprotective against AD pathology in the adult 5XFAD mouse model of AD, was administered to wild-type (WT) female mice mated to heterozygous 5XFAD males during gestation and lactation. Two-month-old 5XFAD male and female offspring of vehicle-treated dams showed memory loss as expected. Remarkably, maternal treatment with TPPU fully prevented memory loss in 5XFAD. TPPU-induced brain epigenetic changes in both WT and 5XFAD mice, modulating global DNA methylation (5-mC) and hydroxymethylation (5-hmC) and reducing the gene expression of some histone deacetylase enzymes (Hdac1 and Hdac2), might be on the basis of the long-term neuroprotection against cognitive impairment and neurodegeneration. In the neuropathological analysis, both WT and 5XFAD offspring of TPPU-treated dams showed lower levels of AD biomarkers of tau hyperphosphorylation and microglia activation (Trem2) than the offspring of vehicle-treated dams. Regarding sex differences, males and females were similarly protected by maternal TPPU, but females showed higher levels of AD risk markers of gliosis and neurodegeneration. Taken together, our results reveal that maternal treatment with TPPU impacts in preventing or delaying memory loss and AD pathology by inducing long-term modifications in the epigenetic machinery and its marks.

Cognitive Decline and BPSD Are Concomitant with Autophagic and Synaptic Deficits Associated with G9a Alterations in Aged SAMP8 Mice.

Behavioural and psychological symptoms of dementia (BPSD) are presented in 95% of Alzheimer's Disease (AD) patients and are also associated with neurotrophin deficits. The molecular mechanisms leading to age-related diseases are still unclear; however, emerging evidence has suggested that epigenetic modulation is a key pathophysiological basis of ageing and neurodegeneration. In particular, it has been suggested that G9a methyltransferase and its repressive histone mark (H3K9me2) are important in shaping learning and memory by modulating autophagic activity and synaptic plasticity. This work deepens our understanding of the epigenetic mechanisms underlying the loss of cognitive function and BPSD in AD. For this purpose, several tasks were performed to evaluate the parameters of sociability (three-chamber test), aggressiveness (resident intruder), anxiety (elevated plus maze and open field) and memory (novel object recognition test) in mice, followed by the evaluation of epigenetic, autophagy and synaptic plasticity markers at the molecular level. The behavioural alterations presented by senescence-accelerated mice prone 8 (SAMP8) of 12 months of age compared with their senescence-accelerated mouse resistant mice (SAMR1), the healthy control strain was accompanied by age-related cognitive deficits and alterations in epigenetic markers. Increased levels of G9a are concomitant to the dysregulation of the JNK pathway in aged SAMP8, driving a failure in autophagosome formation. Furthermore, lower expression of the genes involved in the memory-consolidation process modulated by ERK was observed in the aged male SAMP8 model, suggesting the implication of G9a. In any case, two of the most important neurotrophins, namely brain-derived neurotrophic factor (Bdnf) and neurotrophin-3 (NT3), were found to be reduced, along with a decrease in the levels of dendritic branching and spine density presented by SAMP8 mice. Thus, the present study characterizes and provides information regarding the non-cognitive and cognitive states, as well as molecular alterations, in aged SAMP8, demonstrating the AD-like symptoms presented by this model. In any case, our results indicate that higher levels of G9a are associated with autophagic deficits and alterations in synaptic plasticity, which could further explain the BPSD and cognitive decline exhibited by the model.