Session : Nutrition and Brain Health

Western-style diet consumption is associated with deficits in cognitive processing. We, and others, have implicated microglia in mediating this connection. Our initial investigation revealed that overfeeding during the neonatal period or consumption of a diet high in fat and sugar in advanced age leads to cognitive deficits and microgliosis. We therefore hypothesized that microglial priming (with poor diet or other neuroinflammatory challenges) is detrimental for cognition and that microglial dynamics are important for maintaining cognitive health. We used our unique transgenic rats expressing a diphtheria toxin receptor in the promoter for Cx3cr1, expressed on microglia and macrophages. This model allows us to conditionally, and transiently, ablate microglia and investigate their contribution to diet-induced cognitive changes. Here, we revealed that a high-fat, high-sugar diet leads to cognitive deficits in the aging, but this is not rescued by acute microglial ablation, suggesting microglia’s role in shaping cognitive health is a cumulative one. Our data also support a role for astrocytes in these effects that we continue to investigate. Together these findings suggest the detrimental effect of poor diet on cognition is linked to microglial priming, but that these changes are cumulative and acute microglial manipulations are insufficient to rescue the memory loss.

With the emergence of neurodegenerative diseases such as Alzheimer’s disease, there is a growing demand for neuroprotective compounds. AD is a progressive disease characterized by neuronal loss, the formation of senile plaques and hyperphosphorylation of the protein tau. Our laboratory has previously demonstrated the positive effect of nutraceutical compounds such as omega-3 on cognitive health. Here, macro-algae represent a vector of original molecules whose potential in health applications deserves to be explored. Palmaria Palmata (P. Palmata) is a red macro-alga known to synthesize mycosporin-like amino acids (MAAs). The aim of the present project was to optimize the production of macro-algae, quantify their bioactive MAA content, and then evaluate their distribution and action on brain function in a murine model. Our working hypothesis is that oral intake of P. Palmata would improve the pathology associated with AD. To study the effects of chronic treatment, a mouse model of AD (3xTg-AD) and control mice including both males and females aged 17 months were fed either a diet enriched with P. Palmata extracts (PPE) or a control diet for 8 weeks (4 groups, n=10-21). We assessed markers of neuropathology either by western immunoblot assay (tau protein and kinases) or by ELISA assay of Ab_1-40/42  peptides in mice cortex. Our work first showed that a diet enriched with PPE enabled the detection of four MAAs in mice plasma and in certain organs such as liver and kidney. At 19 months, the behavior of animals was assessed before euthanasia, but no significant effects were observed. Postmortem analyses in the cortex of mice revealed that the extract-enriched diet induced a decrease in levels of phosphorylated (Ser202 and Thr217 sites) and aggregated tau protein, as well as total tau protein, a decrease in Ab_1-40/42  peptides in females, an increase in the levels of a kinase involved in several cellular cascades (PI3K), and other proteins such as apolipoprotein E (ApoE) and choline acetyl transferase (ChAT). Our study suggests that the administration of a diet enriched with PPE can modulate markers associated with AD pathology.

Major depressive disorder (MDD) is one of the most spread psychiatric illnesses in the world. During the last years, several studies have brought forward that the intestinal microbiota could be involved in the disease. Particularly, we showed that a production of indole, a bacterial metabolite produced in the gut from dietary tryptophan, induces anxiety-like and depressive-like behaviors in micea. However, the mechanism of action of indole is still not fully understood. Interestingly, we also showed that absence of the gut microbiota in germ-free mice is associated with changes in the expression of genes encoding receptors and enzymes of the endocannabinoidome (eCBome) as well as changes in eCBome lipid mediator levels in intestinesb and brainc. Furthermore, a key finding has shown that the effect of the gut microbiota on mouse depressive-like behaviors is partly mediated by the endocannabinoid systemd. These results led us to hypothesize that the effect of indole or its derivatives on the host pathophysiology of MDD might be through the eCBome. To test this hypothesis, we designed a study, in which germ-free mice were inoculated either with E. coli producing indole or with a genetically modified E. coli strain unable to produce indole. Then we collected several tissues and fluids including brain, intestines, and blood, where we measured eCBome lipid mediators by LC-MS/MS, intestinal permeability using Ussing chambers as well as feces to carry out other biochemical analyses. The results of this experiment will be presented.

The benefits of plant-derived natural products to promote brain health in ageing and neurodegenerative diseases have been investigated in countless models. However, once bioavailable and circulating in the bloodstream, the specific mechanisms by which natural products interact with cells forming the blood-brain barrier (BBB) remain elusive. The BBB is the gatekeeper of the brain, acting as a molecular and physical barrier separating circulating factors from the brain parenchyma. Therefore, understanding the neuroprotective properties of plant-derived compounds necessitates a better characterization of their dynamic relationships with the brain vasculature. Novel in vitro microfluidic models of the BBB and experimental platforms that leverage human induced pluripotent stem cells (iPSCs) have the potential to address key questions in nutritional neurobiology. For example, a recent study leveraged BBB chips to understand the cellular and molecular mechanisms governing BBB dysfunction in people affected by Parkinson’s disease, and we will explore how these models could help understand how phytomolecules interact with, or even repair this complex neurovascular unit.

Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships with neurons and glial cells among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent repeated social defeat (RSD) or remained non-stressed (controls). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Hippocampal lipidomic analyses was lastly performed. Our results indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our findings reveal novel mechanisms by which a KD might improve the resistance to psychological stress.

Both industry leaders and academic experts will discuss the current challenges and opportunities associated with harnessing food-derived molecules to facilitate healthy aging.