Paper: N-3 PUFA diet enrichment prevents amyloid beta-induced depressive-like phenotype
As studied in BCM 441, polyunsaturated fats (PUFAs) are a main component of neuronal cell membranes, and n-3 and n-6 PUFAs can be released from membranes to play roles in signal transduction either directly or by being converted to various mediators. N-3 PUFAs such as docosahexaenoic acid (DHA) are prevalent in the brain and can modulate synaptic plasticity, carry out neuroprotective roles, and exhibit anti-inflammatory effects while n-6 PUFAs such as arachidonic acid induce inflammation (Luchtman et al., 2016). Due to the cognitive enhancing effects of n-3 PUFAs, these fatty acids are crucial for proper brain development and function, and n-3 PUFA deficient diets have even been linked to symptoms of clinical depression (Colangelo et al,. 2009). In a recent study by Morgese et al. titled, “N-3 PUFA diet enrichment prevents amyloid beta-induced depressive-like phenotype,” lifelong n-3 PUFA rich diets have been shown to demonstrate a preventative role against depression caused by beta-amyloid protein (Morgese et al,. 2017).
Deposition of amyloid beta-peptide plaques (Aß) in the brain is thought by many to be the driving force behind Alzheimer’s disease (AD), which influences other AD-associated pathologies such as neurofibrillary tangles of tau protein and neuroinflammation (Hardy et al,. 2002). Increased Aß levels have also been found in depressed patients, which helps support the theory that depression in elderly patients is common in the first stages of AD and can indicate the onset of AD (Colaianna et al,. 2010). Authors have previously found that injection of Aß in rat cerebrospinal fluid induces depression, marked by low serotonin (5-HT) and neuronal growth factor levels (Colainna et al,. 2010). Due to the neuroproctective roles of n-3 PUFAs, Morgese et al. 2017 hypothesized that n-3 PUFA deficiency may predispose individuals to depression by increasing Aß levels and altering neurotransmission (Morgese et al,. 2017). The authors were the first to evaluate how lifelong n-3 PUFA rich or n-3 PUFA poor diet influenced depressive symptoms induced by Aß administration.
Authors first analyzed the role of lifelong PUFA diets by examining depressive-like phenotypes in rats that were fed a lifelong n-3 PUFA rich diet, n-6 rich PUFA diet, or balanced n-6/n-3 PUFA diet, and then injected with Aß peptides. Depressive-like phenotypes were detected by a forced swimming test (FST), a widely used test in which mice are placed in cylinders filled with water. Mice make immediate attempts to escape, and then give up and become immobile. The immobility time is measured and positively correlated with a state of depression. N-3 PUFA fed rats displayed shorter immobility times and longer swimming times than n-6 PUFA fed or balanced n-6/n-3 PUFA diets. Thus, the authors concluded that n-3 PUFA fed diets prevented Aß-induced depressive like behavior.
To validate and further explain the Aß-induced depression phenotypes detected by the FST, authors obtained neurochemical data by quantifying biological markers of depression. Biological markers were detected in n-3 PUFA fed mice, n-6 PUFA fed mice, and balanced n-6/n-3 PUFA fed mice after being injected with Aß peptides. The authors found higher levels of serotonin (5-HT) in n-3 PUFA fed mice than the other two groups, aligning with the FST result that lifelong n-3 PUFA enriched diets prevent Aß-induced depression. Serotonin deficiency is associated with depression, and this deficiency can be caused by tryptophan’s metabolism into kynurenine (KYN) instead of serotonin due to the cortisol-induced stimulation of the liver enzyme tryptophan 2,3 dioxygenase (Oxenkrug et al,. 2013). Authors measured levels of KYN, and found higher levels of KYN in n-6 PUFA and n-6/n-3 PUFA fed mice, suggesting that this tryptophan metabolism shunt is the cause of reduced serotonin levels in n-3 PUFA deficient diets.
To further investigate PUFA diet on central nervous system function, the authors measured levels of neurotrophins in n-3, n-6 PUFA and n-6/n-3 balanced diets after Aß injection. Neurotrophins are growth factor proteins that regulate neural survival, development, plasticity, and function (Huang et al,. 2009). Two families of neurotrophins are nerve growth factors (NGF) and brain-derived neurotrophic factors (BDNF), and DHA levels are positively correlated with these neurotrophins (Huang et al,. 2009). Morgese et al. have previously found that Aß injection negatively regulates neurotrophin regulation in the prefrontal cortex (PFC) of mice. This result was consistent with n-6 and n-6/n-3 PUFA fed mice since decreased NGF mRNA and BDNF mRNA levels were observed in these groups. However, a lifelong enriched n-3 PUFA diet actually resulted in increased NGF mRNA levels after Aß was administered, while BDNF mRNA levels did not decrease in n-3 PUFA fed mice after injection of Aß. The authors also measured NGF and BDNF protein levels to verify the mRNA quantification results and observed similar patterns. These findings suggest that n-3 PUFA enriched diets prevent Aß-induced depression by safeguarding neurotrophin levels essential for proper brain function.
This is a unique study that examines protective effects of lifelong n-3 PUFA diets in specific regard to Aß-induced depression, which is often a prodromal symptom of AD in elderly patients. N-3 PUFA rich diets prevent Aß-induced depression by maintaining levels of serotonin and increasing production of neurotrophins. These findings support a diet supplemented with n-3 PUFAs as an effective method of warding off depression and other Aß-related symptoms. The complete molecular mechanism underlying the protective effects of n-3 PUFAs needs to be further addressed. In particular, methods of shifting Aß towards the fibril form as opposed to the soluble form needs to be studied since soluble Aß is the most detrimental form (Morgese et al,. 2017). It has previously been shown that n-3 PUFAs in the membrane can cause Aß to favor the lipid bilayer, thus removing it from its soluble form in the cell (Vitiello et al,. 2013). N-3 PUFAs are crucial for proper central nervous system function as discussed in BCM 441, and are rich in flaxseed oil, salmon fat, spinach, walnuts, and soybeans.
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