Role of DHA in aging-related changes in mouse brain synaptic plasma membrane proteome

Abstract

Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane (SPM) proteins supporting synaptic integrity and neurotransmission were down-regulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an important role of DHA in synaptic function. In this study, we demonstrate aging-induced synaptic proteome changes and DHA-dependent mitigation of such changes using mass spectrometry (MS)-based protein quantitation combined with western blot or mRNA analysis. We found significant reduction of 15 SPM proteins in aging brains including fodrin-α, synaptopodin, PSD-95, SV2B, SNAP25, SNAP-α, NR2B, AMPA2, AP2, VGluT1, munc18-1, dynamin-1, VAMP2, rab3A, and EAAT1, most of which are involved in synaptic transmission. Notably, the first nine proteins were further reduced when brain DHA was depleted by diet, indicating that DHA plays an important role in sustaining these synaptic proteins down-regulated during aging. Reduction of two of these proteins was reversed by raising the brain DHA level by supplementing aged animals with an omega-3 fatty acid sufficient diet for 2 months. The recognition memory compromised in DHA-depleted animals was also improved. Our results suggest a potential role of DHA in alleviating aging-associated cognitive decline by offsetting the loss of neurotransmission-regulating synaptic proteins involved in synaptic function.

Ovarian Hormone-Dependent Effects of Dietary Lipids on APP/PS1 Mouse Brain

“…Synapsins are a family of presynaptic proteins that play critical roles in synaptic development, neurotransmitter release, and neural plasticity through phosphorylation-dependent processes (Chi et al, 2003;Menegon et al, 2006;Giachello et al, 2010). Considering the roles of PI3K, PSD95, and synapsin, our results suggest that diets enriched in n-3 LC-PUFA and with different ratios of specific n-6 and n-3 PUFAs modulate the expression of key elements involved in neuroprotective signaling and synaptic transmission in AD mice, consistent with previous reports on the effects of DHA-enriched diets on hippocampal neuronal development (Cao et al, 2009), synaptic function (Cao et al, 2009), synaptic membrane proteins (Calon et al, 2004;Cansev et al, 2008;Sidhu et al, 2016;Herrera et al, 2018), and the restoration of neural plasticity and cognition after brain trauma (Wu et al, 2011). Our present findings indicate that two diets differing in their specific ARA, EPA, DPA, and DHA content, and in the n-6/n-3 PUFA ratio induce divergent changes in the lipidome of AD mouse brains.…”

Reduced acute neuroinflammation and improved functional recovery after traumatic brain injury by α-linolenic acid supplementation in mice

“…This phenomenon has skewed the n-6 to n-3 PUFA ratio, which is about 15:1 in modern diets [ 1 ]. Neuronal membranes preferentially incorporate docosahexaenoic acid (DHA; 22:6n-3), and its deficiency leads to altered gene expression in the mouse brain [ 2 ]. As the brain tissue content of DHA depends on the amount of n-3 PUFA in the diet, decreased n-3 PUFA consumption would translate to DHA deficiency in the brain.…”

Walnut oil improves spatial memory in rats and increases the expression of acid‐sensing ion channel genes Asic2a and Asic4

“…DHA is incorporated into neuronal membrane glycerophospholipids at the sn-2 position and is involved in regulation of numerous neuronal and glial cell processes, including neurogenesis, synaptogenesis, and neurite outgrowth. Because of its high abundance in the brain, DHA supports membrane protein functions impacting on speed of signal transduction and neurotransmission (Sidhu, Huang, Desai, Kevala, & Kim, 2016). DHA modulates neurotransmitter release, gene expression, membrane-bound enzyme and ion channel activity, and synaptic plasticity (Horrocks & Farooqui, 2004).…”