Liam Barry-Carroll

NutriMind - NutriNeuro

Title

Investigating the role of extracellular vesicles in the relationship between n-3 polyunsaturated fatty acid status and cognitive abilities

Introduction

Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) has been proposed as an attractive therapeutic strategy for maintaining cognitive function. Preclinical studies indicate that n-3 PUFAs can partially mitigate the deleterious effects of aged-related cognitive decline in the elderly. Additionally, n-3 PUFAs are crucial during fetal and early postnatal development, as deficiencies during this period can result in cognitive abnormalities that persist into adulthood. Although the mechanisms by which n-3 PUFA status on cognitive health are not fully understood, they appear to affect the interactions between neurons and the brain’s support cells, microglia, leading to altered neuronal activity. This study investigates the role of of extracellular vesicles (EVs) in n-3 PUFA mediated modulation of brain function. EVs are nano-sized, lipid bound particles secreted by all cell types, involved in cellular signalling and pathogenesis. Due to their ability to reflect their cell of origin, plasma-derived EVs are proposed as prognostic and diagnostic biomarkers for various pathologies. This study aims to characterize the impact of n-3 PUFA status on both plasma and brain EV signatures in relation to cognitive abilities.  

Methods

This double-blinded, randomized, and placebo-controlled study involved 80 healthy individuals aged 60-70 years, who underwent a 12-month supplementation with 340 mg of n-3 PUFAs. Plasma collection and cognitive evaluations were performed before and after supplementation. EVs were isolated from plasma and analyzed using nanoscale flow cytometry to investigate the surface expression of CD9 and CD41. To understand the impact of n-3 PUFA deficiency, mice were fed diets either deficient or sufficient in n-3 PUFAs from gestation until 3 months old. EV extracts from the whole brain were assessed using proteomic analysis and applied to microglia in vitro to evaluate their functional impact.  

Results

Dietary n-3 PUFA supplementation significantly improved visuospatial working memory and increased circulating levels of docosahexaenoic acid (DHA) in elderly individuals. A notable reduction in the percentage of EVs expressing CD9 and CD41 (markers of platelet-derived EVs) was observed in a subset of individuals receiving n-3 PUFA supplementation, which negatively correlated with their memory performance. This suggests that increased n-3 PUFA consumption modulates platelet activity, associated with improved brain function. In mice, brain-derived EVs from n-3 PUFA sufficient and deficient diets contained differentially expressed proteins related to synaptic remodeling and metabolic pathways. These EVs had opposing effects on microglia in vitro, with n-3 sufficient EVs promoting a pro-proliferative response, whereas n-3 deficient EVs increased microglial phagocytic activity.  

Discussion

These findings suggest that dietary n-3 PUFAs modulate the signatures of plasma and brain-derived EVs, associated with changes in EV functionality that may mediate neuronal activity linked to cognitive function.