Brandon's Biochemistry Blog

BCM 441 Spring 2018

N-3 PUFA rich diets reduce risk of developing symptoms of clinical depression: Eat your n-3 PUFAs, and depressive symptoms may only be “super fish oil”

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.








  1. Luchtman, Dirk W., and Cai Song. “Cognitive Enhancement by Omega-3 Fatty Acids from Child-Hood to Old Age: Findings from Animal and Clinical Studies.” Neuropharmacology, Cognitive Enhancers: molecules, mechanisms and minds, 64 (January 1, 2013): 550–65.


  1. Colangelo, Laura A., Ka He, Mary A. Whooley, Martha L. Daviglus, and Kiang Liu. “Higher Dietary Intake of Long-Chain ω-3 Polyunsaturated Fatty Acids Is Inversely Associated with Depressive Symptoms in Women.” Nutrition 25, no. 10 (October 1, 2009): 1011–19.


  1. Morgese, M. G., S. Schiavone, E. Mhillaj, M. Bove, P. Tucci, and L. Trabace. “N-3 PUFA Diet Enrichment Prevents Amyloid Beta-Induced Depressive-like Phenotype.” Pharmacological Research, December 5, 2017.


  1. Hardy, John, and Dennis J. Selkoe. “The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics.” Science 297, no. 5580 (July 19, 2002): 353–56.


  1. Colaianna, M, P Tucci, M Zotti, Mg Morgese, S Schiavone, S Govoni, V Cuomo, and L Trabace. “Soluble Βamyloid1-42: A Critical Player in Producing Behavioural and Biochemical Changes Evoking Depressive-Related State?” British Journal of Pharmacology 159, no. 8 (April 1, 2010): 1704–15.


  1. Oxenkrug, Gregory. “Serotonin-Kynurenine Hypothesis of Depression: Historical Overview and Recent Developments.” Current Drug Targets 14, no. 5 (May 1, 2013): 514–21.


  1. Huang, Eric J, and Louis F Reichardt. “Neurotrophins: Roles in Neuronal Development and Function.” Annual Review of Neuroscience 24 (2001): 677–736.


  1. Vitiello, Giuseppe, Sara Di Marino, Anna Maria D’Ursi, and Gerardino D’Errico. “Omega-3 Fatty Acids Regulate the Interaction of the Alzheimer’s Aβ(25–35) Peptide with Lipid Membranes.” Langmuir 29, no. 46 (November 19, 2013): 14239–45.


  1. This paper is very interesting linking diet and disease. The authors clearly explored the protective nature of n-3 PUFAs in the context of depression and possibly AD, over what they describe as a life-long diet. What is interesting to me is how flexible n-3 PUFAs are in their protective role, and whether or not they can be administered like a treatment. Authors clearly state the preventative aspects, but can amyloid-beta peptide plaques be treated with n-3 PUFAs to demonstrate something similar to a curative role. Great find!

    • admin

      February 11, 2018 at 11:36 pm

      Thank you for the comment, Will. It would be nice if AD patients could be prescribed n-3 PUFAs to rid AD, but n-3 PUFAs along with other dietary and behavioral influences are all mainly prophylactic. The amyloid-beta and neurofibrillary tangle accumulations cannot be reversed. Even though there is no current cure for AD, however, AD patients can be treated with strategies that reduce AD symptoms. Inflammation, a primary symptom of AD, can be reduced by consuming n-3 PUFAs and a Mediterranean-type diet. It would also be convenient if someone created a way to shuttle NSAIDs through the blood-brain barrier to target neuroinflammation, perhaps by conjugating NSAIDs to peptoids. I believe that an n-3 PUFA rich diet will help strengthen cell membranes and revert low serotonin and neurotrophin levels, which may limit symptoms and be recommended by doctors to AD patients. However, an n-3 PUFA diet and other behavioral factors are mainly prophylactic and will do much more justice if consumed lifelong to prevent depression and AD.

  2. Nice title, and another great reason to eat your PUFAs. I was wondering how ‘plastic’ the response to supplementation with n-3 PUFAs is. Mechanistically, do the authors know whether or not the PUFAs are directly decreasing the amount of soluble beta-amyloid, or does lifelong supplementation simply bolster other systems that take care of the beta-amyloid. Would this supplementation be viable for the baby boomers who haven’t grown up eating their n-3 PUFAs?

    • admin

      February 12, 2018 at 12:10 am

      Thank you for the comment, Andrew. There are different mechanisms at play that link n-3 PUFAs to decreased depression and AD. Prophylactically, n-3 PUFAs reduce inflammation and can strengthen neural connections. A theory that directly links n-3 PUFAs and beta-amyloid plaques involves the chemical composition of n-3 PUFA rich membranes. Long term consumption of n-3 PUFAs increases the n-3 PUFA concentration, especially DHA, in the plasma membrane. N-3 PUFAs in the membrane lowers the rigidity and can better accommodate beta-amyloid peptides which can be internalized in the membrane. This decreases the concentration of soluble beta-amyloid peptides wreaking havoc in the CNS. Anyone at any time can benefit from n-3 PUFA supplementation, but the benefits are much more evident in lifelong consumption due to time being a factor as to how much n-3 PUFAs can integrate into plasma membranes. However, faster acting effects such as a decrease in inflammation may still prove beneficial, even to baby boomers who haven’t grown up eating their n-3 PUFAs.

  3. Great spotlight Brendan! It really highlighted the important aspects of the paper. I understand that this information can potentially be used to make different lifestyle choices, in terms of what we eat. Though, the authors did not mention how it can be used clinically. For example, if someone has a genetic mutation predisposing them to AD, is there any way n-3 PUFAs can be used in preventative manor? Should the authors have explored more application options? What do you think? Overall, though, this paper is very high impact and is setting a stage for more ways PUFAs affect our lives and health.

    • admin

      February 12, 2018 at 12:50 am

      Hi Brittany! I appreciate the thought. There were several papers out that explored n-3 PUFA supplementation with depression treatments. N-3 PUFA supplementation proved to be clinically beneficial in this regard, but these studies did not specifically target beta-amyloid induced depression, as discussed in the paper this post was written on. This paper explores prodromal AD symptoms in the form of depression, and n-3 PUFA rich diets proved to serve a protective role of beta-amyloid induced depression. I would imagine that n-3 PUFAs will have this protective role against beta-amyloid related pathologies whether a patient has a mutation that predisposes them to AD or not. However, the benefits of n-3 PUFA diets may be reduced if the mutation causes an early onset of AD. This is because long term consumption of n-3 PUFAs is needed for them to integrate in the plasma membrane to generate their full therapeutic effect.

  4. Hi Brandon,
    This was such an interesting article and you did a great job summarising the important concepts. It’s cool seeing a connection between something we’ve learned in class, PUFAs, and two diseases that are widely prevalent. From what the authors are suggesting, it seems that n-3 PUFA deficiency leads to increased susceptibility to depression and Alzheimer’s disease. In their study, they looked at the lifelong beneficial effects of consuming n-3 PUFAs, which is a preventative measure. Do you think that increasing intake of n-3 PUFAs could be both preventative and curative? In other words, would it be possible to start consuming more n-3 PUFAs after the disease has been found and have that help? In their discussion, they note that in previous research, supplementing with n-3 PUFAs decreased levels of interleukin 6 (shown to be involved in depression). Do you think that this knowledge coupled with some other treatment could be used as a potential cure?

    • admin

      February 12, 2018 at 3:45 pm

      Thank you for the thought, Lily. Yes, increasing n-3 PUFA intake can be both preventative and curative, but more so the former than the latter. N-3 PUFA deficiency increases beta-amyloid peptide levels, decreases serotonin levels, decreases neurotrophin levels, and increases pro-inflammatory mediators such including interleukins. Authors demonstrated that beta-amyloid induced symptoms can be prevented by already having a large supply of n-3 PUFAs, so n-3 PUFA consumption and a healthy lifestyle are key factors to avoid symptoms. However, the progression of AD is not reversible and there is no cure, so only symptoms may be treated. N-3 PUFAs can be used reduce inflammatory symptoms in AD patients, and several studies have shown that depression treatments supplemented with n-3 PUFAs can be beneficial.

  5. This paper seemed to have a lot to unpack given its multiple topics covered of biochemistry, diet, behavior, and neuroscience. I was wondering if you could elaborate on the negative regulation of neurotrophin by A-beta peptide. Did the authors describe a biochemical method of regulation, or were the two factors just correlated. You seem to hint at a mechanism when you use the word “safeguard” in describing A-beta’s role in neurotrophin homeostasis so I’m just wondering if the authors gave any indication of what exactly the “safeguarding” role is. A very intriguing and (potentially) helpful read!

    • admin

      February 12, 2018 at 8:15 pm

      Hi Suzi! When I said “safeguard,” I was referring to how n-3 PUFA rich diets prevent the decrease of neurotrophins NGF and BDNF when beta-amyloid peptides were administered. The authors demonstrated in a previous study that soluble beta-amyloid peptides inhibited the expression of NGF and BDNF, but unfortunately beta-amyloid pathology is extremely complex and there is still much to be learned from it, including a succinct mechanism for how soluble beta-amyloids actually decrease NFG and BDNF levels.

  6. Hi Brandon,

    Great paper and clever title. The high impact of this paper is elucidated in integrating the different fields of biochemistry, public health and behavioral science. It is interesting how the authors linked the amount of serotonin 5-HT (and therefore depression) to n-3 PUFAs . Considering this positive relationship however, do you expect that an excess of n-3 PUFAs can be as detrimental as a deficiency in them? For example, an excess in serotonin production in humans has historically been linked to agitation and mood induction; thus, would it be reasonable to predict that consuming a diet with a high n-3/n-6 ratio would also have its own (maybe less severe) problems?

    • admin

      February 12, 2018 at 8:38 pm

      Great question, John. I recall that too little serotonin can cause depression, but too much serotonin can be linked to schizophrenia. As far as I know, an upper limit for how much n-3 PUFAs should be consumed has not been found yet. Although I have read that a large amount of n-3 PUFAs can interfere with the immune system. I would imagine that anti-inflammatory effects of n-3 PUFAs would hinder the ability of the immune system to trigger an inflammatory response to a site of infection. It’s safe to say that too much of one thing is bad.

  7. A great review, especially with the recent interest in omega-3 in the nutritional community. Also, the link between the amyloid-beta peptides and depression is definitely something of note given its link to Alzheimer’s disease. Based on the anti-inflammatory effects of n-3 PUFAs, what other diseases do you think a diet high in omega-3s could be used as a preventative measure of?

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