Most neurological disorders are characterised by multiple factors, in which environmental and genome interaction is considered to play a pivotal role. Dietary elements are significantly gaining attention with regards to their role as essential modifiers of brain function and plasticity (Gomez-Alamillo et al., 2003: pp.831-836). The Omega-3 family consists of essential fatty acids characterised by a double bond present 3 atoms away from the terminal methyl group, play a pivotal part in many of the necessary bodily functions (Kaur et al., 2014: p.2289). In terms of the brain, Omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are important modulators of neurogenesis, neuroinflammation, oxidative stress, and key constituents of neuronal membranes (Danthiir et al., 2011: p.2; Denis et al., 2015: p.139). DHA in particular has a significant role in promoting brain plasticity and cognitive function and accumulates rapidly in brain tissue during infancy. However, DHA cannot be synthesised by the body or brain itself and thus, must be obtained through diet – directly through fish oils, terrestrial meats and eggs, or indirectly through the metabolisation of short-chain Omega-3 (Bhatia et al., 2011: p.1; Simopoulos, 2016: p.4). DHA deficiency is linked to a plethora of neurological disorders therefore this review aims to explore the current understanding of the mechanisms of DHA signalling, it’s role in cognition, and potential as a therapeutic target.
Mechanisms of DHA action
DHA has multiple actions and therefore acts through multiple mechanisms. The actions of DHA are mediated through surface or intracellular fatty acid receptors such as peroxisome proliferator-activated receptors (PPARs), NFkB, and G-protein coupled surface receptors or through changes in the composition of cell membrane phospholipids (figure 1)(Calder, 2012: pp.592-599). Research has highlighted that DHA signalling occurs through the retinoid X receptor (RXR) pathway; a crucial pathway in the promotion of brain cognition and plasticity. Such studies have revealed that DHA is a direct ligand of PPARy, whereupon DHA binding PPARy heterodimerises with RXR along with different co-activators (CREB). It was demonstrated that PPARy and it’s known target genes were induced by DHA in dendritic cells and as a result, there was a decrease in the production of inflammatory cytokines TNFα and IL-6 upon endotoxin stimulation (van Neerven et al., 2008: p.436; Viswakarma et al., 2010: p.2). Therefore, through PPARy activation DHA can have effects on gene expression and thus on translation and expression of numerous proteins, particularly those involved in inflammation (Calder, 2012: p.595). DHA regulates the activity of PPARy/RXR and promotes brain plasticity and cognition through decreased inflammation and improved motoneuron survival. This has led to the belief that DHA supplementation has numerous health benefits and should be adopted by many. However, recent research has associated an increase in PPARy activation and an adverse effect on the cardiovascular system such as congestive heart failure and myocardial infarction (Chandra et al., 2017: p.4) which could make therapeutically targeting this particular pathway controversial.
Figure 1. A brief schematic of mechanisms of DHA action with model for ligand induced PPARy/RXR activation. Upon DHA binding, the PPARy/RXR undergoes a change in conformation and recruits co-activators (e.g. CREB) which allows binding to the target gene and induces pro-plasticity and pro-cognition in the brain (adapted from Calder, 2016: p.17 & Wei et al., 2012: p.106)
DHA and cognition
Humans reach peak cognitive function around the middle of adulthood and most research on the effects of DHA on cognitive function are centred around cases of DHA-deficiency or cognitive impairment. In healthy adults (35-54 years old) with no prior supplementation of DHA, studies have demonstrated a positive correlation between higher blood levels of DHA and improved non-verbal reasoning, memory, mental flexibility and vocabulary (Muldoon et al., 2010: p.848). Additionally, in adults with low physical activity, higher DHA levels were shown to counteract the negative effects on memory (Leckie et al., 2014: p.1). These are key findings as physical activity enhances grey matter volumes in the brain reducing the risk for Alzheimer’s disease (AD) (Erickson et al., 2012: pp.615-621). As humans age, inflammation, oxidative stress increases, and total grey matter decreases along with a matched decrease in DHA composition in the brain (Resnick et al., 2003: p.3298). Ageing has also been correlated with a decrease in PPARy expression and activity (Ulrich-Lai and Ryan, 2013: p.4). However, DHA intake has been positively correlated with an increase in grey matter volume and PPARy expression in areas of the brain that is responsible for cognition in elderly adults (Conklin et al., 2007: p.209; Raji et al., 2014: p.1). Overall, research has demonstrated a significant positive effect of dietary DHA supplementation and overall blood DHA concentration on cognition in normal ageing adults thus supporting the argument for DHA dietary supplementation during ageing (Nilsson et al., 2012: pp.1-9; Strike et al., 2016: pp.236-242; Tokuda et al., 2015: pp.633-644).
It is well documented that DHA levels in the brain decline with age which is thought to be due to resources primarily used for normal cellular maintenance being redirected for cellular repair following the cumulative effects of inflammatory, oxidative, and various other environmental insults (Erickson et al., 2012: p.1). Various factors contribute to cognitive function and neuroplasticity during adulthood including brain-derived neurotrophic factor (BDNF). BDNF has anti-inflammatory activity and is associated with enhanced mitochondria activity and synaptic plasticity, and BDNF expression and signalling is increased through environmental factors – DHA (Giacobbo et al., 2019: 3295-3312). Research has demonstrated that DHA induces PPARy which in turn promotes BDNF, and down-regulated PPARy and BDNF have been identified in several neurological diseases characterised by cognitive impairment – AD and dementia (d’Angelo et al., 2019: p.2). Other than neuroinflammation a key characteristic of AD is increased amyloid-β peptides (Aβ) which aggregate and form plaques on the brain tissue leading to significant cognitive impairment (Zhang et al., 2019: p.1). The PPARy/RXR pathway has been demonstrated to regulate Aβ and therefore, the addition of DHA attenuates Aβ production through activation of PPARy (Govindarajulu et al., 2018: p.4). Thus, DHA demonstrates a significant protective effect against neurodegenerative disorders through multiple mechanisms.
Therapeutic approaches
Many neurological disorders are challenging and have no cure or fully established preventative treatments. DHA shows therapeutic and preventative potential for those at risk of developing or suffering from such neurological disorders. Despite the therapeutic benefits of DHA recent research has published that supplementation of DHA is linked to adverse cardiac events such as myocardial infarctions and heart failure (Chandra et al., 2017: p.4). Therefore, the treatment for neurological disorders such as AD may be more beneficial if it improved the ability of the brain to utilise existing DHA. For example, the PPARy/RXR complex activates Apolipoprotein E (apoE) which aids in clearing Aβ (Bonet-Costa et al., 2016: p.701). A mutated version of apoE – ApoE4 – is the most prevalent genetic risk factor for developing AD resulting in Aβ accumulation which has been shown to limit the delivery of DHA to the brain. Various apoE4-targeted therapeutic approaches have been developed. These include reversal of hypo-lipidation of apoE4, anti-immunotherapy which generates antibodies against apoE4, apoE-directed anti-amyloid treatment, apoE mimetics, and the most promising and novel approach – gene editing apoE4 into apoE3/2 which is an ideal candidate as the nucleotide difference is only 1 (Safieh et al., 2019: pp.7-10). However, for translation into a human clinical setting further research into the specificity of such methods and advances in animal model studies is required. These approaches also pose the question as to whether this type of treatment can be curative as currently, its greatest potential lies in delaying the onset and progression of neurodegenerative diseases.
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