Dietary phospholipids: Role in cognitive processes across the lifespan

peer-reviewedChronic stress and ageing are two of the most important factors that negatively affect cognitive processes such as learning and memory across the lifespan. To date, pharmacological agents have been insufficient in reducing the impact of both on brain health, and thus, novel therapeutic strategies are required. Recent research has focused on nutritional interventions to modify behaviour and reduce the deleterious consequences of both stress and ageing. In this context, emerging evidence indicate that phospholipids, a specific type of fat, are capable of improving a variety of cognitive processes in both animals and humans. The mechanisms underlying these positive effects are actively being investigated but as of yet are not fully elucidated. In this review, we summarise the preclinical and clinical studies available on phospholipid-based strategies for improved brain health across the lifespan. Moreover, we summarize the hypothesized direct and indirect mechanisms of action of these lipid-based interventions which may be used to promote resilience to stress and improve age-related cognitive decline in vulnerable populations.Science Foundation Irelan

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Aß Facilitates LTD at Schaffer Collateral Synapses Preferentially in the Left Hippocampus

Summary: Promotion of long-term depression (LTD) mechanisms by synaptotoxic soluble oligomers of amyloid-β (Aß) has been proposed to underlie synaptic dysfunction in Alzheimer’s disease (AD). Previously, LTD was induced by relatively non-specific electrical stimulation. Exploiting optogenetics, we studied LTD using a more physiologically diffuse spatial pattern of selective pathway activation in the rat hippocampus in vivo. This relatively sparse synaptic LTD requires both the ion channel function and GluN2B subunit of the NMDA receptor but, in contrast to electrically induced LTD, is not facilitated by boosting endogenous muscarinic acetylcholine or metabotropic glutamate 5 receptor activation. Although in the absence of Aß, there is no evidence of hippocampal LTD asymmetry, in the presence of Aß, the induction of LTD is preferentially enhanced in the left hippocampus in an mGluR5-dependent manner. This circuit-selective disruption of synaptic plasticity by Aß provides a route to understanding the development of aberrant brain lateralization in AD

ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning

Long-term memory formation is regulated by many distinct molecular mechanisms that control gene expression. An emerging model for effecting a stable, coordinated pattern of gene transcription involves epigenetic tagging through modifications of histones or DNA. In this study, we investigated the regulation of histone phosphorylation in the hippocampus by the ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway. We found that activation of ERK/MAPK in vitro significantly increased histone H3 phosphorylation in hippocampal area CA1. Furthermore, we found that contextual fear conditioning in vivo leads to a rapid time-dependent increase in histone H3 phosphorylation in area CA1. This increase paralleled the time course of contextual fear-dependent activation of ERK, and was inhibited in vivo by a latent inhibition paradigm as well as by injection of an N-methyl-d-aspartic acid receptor (NMDA-R) antagonist. Finally, injection of an inhibitor of MEK (MAP kinase/ERK kinase), the unique dual-specificity kinase upstream of ERK, blocked the increase in histone H3 phosphorylation seen after contextual fear conditioning. These results demonstrate that changes in histone phosphorylation in the hippocampus are regulated by ERK/MAPK following a behavioral fear conditioning paradigm