Effects of Sex and Western Diet on Spatial Lipidomic Profiles for the Hippocampus, Cortex, and Corpus Callosum in Mice Using MALDI MSI.

Diet is inextricably linked to human health and biological functionality. Reduced cognitive function among other health issues has been correlated with a western diet (WD) in mouse models, indicating that increases in neurodegeneration could be fueled in part by a poor diet. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) to spatially map the lipidomic profiles of male and female mice that were fed a high-fat, high-sucrose WD for a period of 7 weeks. Our findings concluded that the cortex and corpus callosum showed significant lipid variation by WD in female mice, while there was little to no variation in the hippocampus, regardless of sex. On the other hand, lipid profiles were significantly affected by sex in all regions. Overall, 83 lipids were putatively identified in the mouse brain; among them, HexCer(40:1;O3) and PE(34:0) were found to have the largest statistical difference based on diet for female mice in the cortex and corpus callosum, respectively. Additional lipid changes are noted and can serve as a metric for understanding the brain's metabolomic response to changes in diet, particularly as it relates to disease.

Ketogenic diet and BHB rescue the fall of long-term potentiation in an Alzheimer's mouse model and stimulates synaptic plasticity pathway enzymes.

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-ß (Aß) 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.

Elevated lipopolysaccharide binding protein in Alzheimer's disease patients with APOE3/E3 but not APOE3/E4 genotype.

Introduction: The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood. Methods: In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA. Results: LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS). Discussion: These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.