Background

Women represent the majority of Alzheimer's disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still unknown.

Methods

To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me3, H3K27ac, and H3K27me3 in brain cortexes of an Alzheimer mouse model (PSAPP). Gastrocnemius muscles were also tested since they are known to be different in the two sexes and are affected during the disease progression.

Results

Correlation analysis distinguished the samples based on sex for H3K4me3 and H3K27me3 but not for H3K27ac. The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me3 distribution on the X chromosome which showed sex-related differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes.

Conclusions

H3K4me3, H3K27ac, and H3K27me3 signals are slightly affected by sex in brain, with the exception of H3K27me3, while a higher number of differences can be found in gastrocnemius.

The signaling molecule p66Shc is often described as a longevity protein. This conclusion is based on a single life span study that used a small number of mice. The purpose of the present studies was to measure life span in a sufficient number of mice to determine if longevity is altered in mice with decreased Shc levels (ShcKO). Studies were completed at UC Davis and the European Institute of Oncology (EIO). At UC Davis, male C57BL/6J WT and ShcKO mice were fed 5% or 40% calorie-restricted (CR) diets. In the 5% CR group, there was no difference in survival curves between genotypes. There was also no difference between genotypes in prevalence of neoplasms or other measures of end-of-life pathology. At 40% calorie restriction group, 70th percentile survival was increased in ShcKO, while there were no differences between genotypes in median or subsequent life span measures. At EIO, there was no increase in life span in ShcKO male or female mice on C57BL/6J, 129Sv, or hybrid C57BL/6J-129Sv backgrounds. These studies indicate that p66Shc is not a longevity protein. However, additional studies are needed to determine the extent to which Shc proteins may influence the onset and severity of specific age-related diseases.

The Ketogenic Diet (KD) improves memory and longevity in aged C57BL/6 mice. We tested 7 months KD vs. control diet (CD) in the mouse Alzheimer's Disease (AD) model APP/PS1. KD significantly rescued Long-Term-Potentiation (LTP) to wild-type levels, not by changing Amyloid-β (Aβ) levels. KD's 'main actor' is thought to be Beta-Hydroxy-butyrate (BHB) whose levels rose significantly in KD vs. CD mice, and BHB itself significantly rescued LTP in APP/PS1 hippocampi. KD's 6 most significant pathways induced in brains by RNAseq all related to Synaptic Plasticity. KD induced significant increases in synaptic plasticity enzymes p-ERK and p-CREB in both sexes, and of brain-derived neurotrophic factor (BDNF) in APP/PS1 females. We suggest KD rescues LTP through BHB's enhancement of synaptic plasticity. LTP falls in Mild-Cognitive Impairment (MCI) of human AD. KD and BHB, because they are an approved diet and supplement respectively, may be most therapeutically and translationally relevant to the MCI phase of Alzheimer's Disease.