Summary:
Complementary preventive therapy for Alzheimer’s disease should include DHA for its biochemical implications, especially in apoE4-genotype obese-diabetic patients. DHA mechanisms involve reducing adiposity and secretions, improving insulin sensitivity, guarding against oxidative stress, and guarding against beta-amyloid plaque, neurofibrillary tangles and advanced glycation end-products.
Background: Urgent Call for Alzheimer’s Disease Preventive Therapies
Foresight warns that the present epidemic of obesity and diabetes in the United States of America will lead to future medical epidemics and among them will be Alzheimer’s disease (AD), the most common neurodegenerative disease seen in aging. AD is seriously debilitating and at present time has no cure. Current treatments are limited to cholinesterase inhibitors to improve function of signaling pathways in memory, but are not intended to prevent or slow further brain damage. Preventive strategies are currently being studied to assist in avoiding Alzheimer-type dementia in the population. Obese-diabetic persons are predisposed to AD, particularly if they are of the apoE4 genotype (Luchsinger & Gustafson, 2009). ApoE4-genotype obese-diabetic individuals, at high risk for AD, represent an ideal population for testing AD-prevention therapies. The last decade has witnessed popularity of researching fish-derived omega-3 fatty acids, notably docosahexaenoic acid (DHA), and their relationship with brain health. New research has begun to associate the use of fish oil with less cognitive decline and lowered risk of AD (Martin, 2008). Along with dieting and exercise directed at improving insulin sensitivity, DHA intake in apoE4-genotype obese-diabetic subjects may reduce the progression of AD. The following are four potential mechanisms that could explain how DHA operates: (a) improving insulin sensitivity to reduce continual hyperglycemia, hyperinsulinemia, and hypertension (b) inhibition of beta-amyloid (Abeta) and plaque production, (c) inhibition of hyperphosphorylation of tau protein, which leads to neurofibrillary tangle formation, and (d) reduction of oxidative stress and advanced glycation end-product (AGE) formation and cross-linking. This paper will discuss the literature supporting this hypothesis.
Biochemistry of AD
The underlying condition seen with AD is impairment of memory and learning, or dementia. It is primarily caused by Abeta plaques. At the core of the plaques is amyloid protein. Autopsy of AD brains shows that plaques are widely distributed over the cerebral cortex. The Abeta aggregates when under oxidative stress, which worsens the AD (Carr, Goate, Phil, & Morris, 1997). The Abeta protein binds to proteases inhibitors suppressing the normal catabolism of proteases, which allows them to damage neurons and other proteins. Neurofibrillary tangles are a secondary factor induced by Abeta. They become localized mainly in the hippocampus, entorhinal cortex and amygdala. The tangles are made up of the tau protein. Tau protein is one of the microtubule associated proteins used to stabilize microtubules and for providing attachment to other cells. The tangles are produced by abnormal hyperphosphorylation of the tau protein. The protein when hyperphosphorylated, also called “paired helical filaments,” becomes aggregated. Neurons affected by plaques and tangles eventually die (Carr et al., 1997). As described before, the tangled up mess causes considerable interference and attenuates damage in the brain. The tangles are susceptible to glycation. Advanced glycation end-products (AGEs) and cross-linking occur. The AGEs are formed by nonenzymatic Maillard reactions, when glucose molecules open and attach to lysine in proteins producing Schiff bases, which form Amadori products. The Amadori products—as also found in glycated hemoglobin—are more stable, but when attacked by free radicals produce oxoaldehydes, otherwise called AGEs. Glycations alter function of proteins causing their degradation. The Maillard reactions also lead to production of reactive oxygen species, which, in turn, promote more glycation (Kikuchi et al., 2003). Glycation on tau protein enhances formation of tangles and is thought to enhance aggregation of Abeta (Sasaki et al., 1998). The AGEs also activate glia producing inflammation and dysfunction as well as fragmentation into glyoxal and methylglyoxal (Kuhla et al., 2005). Thereby, AGEs are implicated as a cause of inflammation, oxidative stress, neuronal dysfunction (Yan et al., 1995). The Abeta aggregation, tangles and AGE cross-linking are ultimately cause for AD pathogenesis.
ApoE4 Genotype
Apolipoproteins are proteins that form lipoproteins to transport fats in the blood stream. They are produced in the liver and their amount in the bloodstream is reflective of dietary fats. An apolipoprotein involved with chylomicron transport across the blood-brain barrier is apolipoprotein E (apoE). These apoE proteins are also found along with Abeta in plaques and along with tau proteins in neurofibrillary tangles. Genetic variations of ApoE are associated with risk of AD. The allele variation episilon2 (E2) appears to be protective while episilon3 is protective to a lesser extent; however, the variant epsilon4 (E4) allele or two alleles has been found to increase AD risk 2.5-fold and 5.6-fold, respectively (Martins, Oulhaj, de Jager, & Williams, 2005; Scarmeas et al., 2002). The E4 allele is not a cause of AD, but predisposes individuals to risk.ApoE4 genotype individuals have increased susceptibility to developing Abeta plaques and neurofibrillary tangles. The mechanism is thought to be dependent on lipidated apoE4. It binds to a specific receptor, apoER2, in brain cells more easily than the other alleles. The receptor allows endocytosis of apoE4 as well as amyloid precursor protein and beta-secretase. Beta- and gamma-secretases then fragment the proteins (He, Cooley, Chung, Dashti, & Tang, 2007). The amyloid precursor protein is fragmented to Abeta. Presence of ApoE4 is also thought to slow clearance of occurring Abeta in the brain. Lipoprotein receptor-related protein-1 (LRP1) is an Abeta-binding molecule that clears Abeta at the blood-brain barrier. Abeta-apoE2 or Abeta-apoE3 complexes are cleared at a much faster rate than Abeta-apoE4 complexes (Deane et al., 2008). These factors lead to risk of “early onset” AD, which is defined as those with AD before age 65. ApoE4 genotype can lead to development of AD as early as ages 30 and 40, especially if obese and diabetic. The apoE4-genotype obese-diabetic population represent ideal candidates for study of AD preventive strategies.
AD Risk Increased by Adiposity and Hyperinsulinemia
Obesity has been consistently linked to the development of dementia and AD (Salihu, Bonnema, & Alio, 2009; Razay, Vreugdenhil, & Wilcock, 2006). Elevated adiposity promotes insulin resistance, an increase of adipokines (cytokines produced from adipocytes) including resistin and tumor necrosis factor-alpha (TNFα). The insulin resistance exacerbates the process leading to metabolic syndrome and diabetes. When obesity is combined with diabetes, the risk of AD increases more than four-fold (Pasinetti et al., 2007). Diabetes and glucose intolerance occurs once the amount of insulin is not enough to overcome elevated plasma glucose. The pancreas secretes more insulin to abnormally high levels to maintain adequate glucose levels in the blood. Abnormal insulin signaling in the brain leads to prolonged elevated insulin levels. Normally insulin would bind to insulin receptors. Under conditions of AD, however, neurons have few insulin receptors and are resistant to insulin. Elevated insulin in the brain that is unable to bind to neurons accumulates in the serum. Hyperinsulinemia stimulation of inflammation is thought to induce formation of Abeta plaques. The loss of appropriate insulin signaling alters activity of phosphorylation leading to increased phosphorylation of tau proteins (Schubert et al., 2004). Prolonged levels of elevated insulin was also suggested by at least one study to peripherally stimulate abnormal signal transduction pathways causing hyperphosphorylation of tau proteins (Freude et al., 2005). The hyperphosphorylation and formation of Abeta plaques caused by hyperinsulinemia in the brain are major factors leading to AD.
Elevated insulin interferes with Abeta degradation. Insulin-degrading enzyme (IDE) breaks down both insulin and Abeta. In addition, it breaks down amylin, which is another amyloidogenic peptide. With all three substrates—insulin, Abeta and amylin competing for the same enzyme—less Abeta and amylin is broken down (Qiu & Folstein, 2006). ApoE4 is also thought to possibly downregulate IDE expression in neurons because it binds to its receptor (Du, Chang, Guo, Zhang, & Wang, 2009). A present target for AD preventive therapy may be to help increase effectiveness of IDE with drugs or by preventing hyperinsulinemia.
Clearance of Abeta is also affected by elevated insulin. The abnormal insulin signaling and inappropriate neuron function causes reduced levels of transthyretin. Transthyretin is a protein that normally supports transport of Abeta out of brain. Therefore, Abeta and amylin elevate in the plasma and becomes aggregated in the environment of inflammation forming plaques (Qiu & Folstein, 2006). In one prospective study, hyperinsulinemia was found to double the risk of AD in subjects ages 65 and older in Manhattan (Luchsinger, Tang, Shea, & Mayeux, 2004). Therefore, the indirect effects of elevated insulin on the brain is one more reason to closely monitor plasma glucose in both diabetics and metabolic syndrome.
Hyperinsulinemia also increases the risk of hypertension. Insulin stimulates sodium reabsorption in the kidneys and causes vasoconstriction that can lead to elevated blood pressure (Ritz, 2008). A seven-year longitudinal study found diabetics patients who had hypertension have a six-fold increased risk of AD (Posner et al., 2002). Hypertension may be involved mainly in progression of AD by producing dysfunction in the blood-brain barrier as well as increasing oxidative stress (Skoog, 1997). Increased permeability in the blood-brain barrier is thought to create greater transport of Abeta across the barrier and less to leave the brain. The oxidative stress presents additional effects by promoting glycation.
Hyperglycemia naturally increases glycation in the brain. Combined with oxidative stress, the excess glucose lead to rapid progression of AGEs (Sato et al., 2006), which can be attenuated by AGEs found in the diet (Gil & Bengmark, 2007). Increased glyoxal levels, resulting from fragments of amadori products, also inactivates enzymes such as superoxide dismutase, needed for neutralizing free radicals, promoting more aggregation, more glycation and more damage to cells (Jabeen, Saleemuddin, Petersen, & Mohammad, 2007). Formation of AGEs and occurrence of AGEs cross-linking neurofibrillary tangles and Abeta aggregates limits neuronal function, produces oxidative stress, increases susceptibility to oxidative stress, and leads to neuronal apoptosis.
Mechanisms of DHA Against AD
The human brain is made up of approximately 60 percent fatty acids. PUFAs make up a major portion of which DHA is in greatest amount followed by EPA. The greatest concentration of DHA in the nervous system is in the membrane phospholipids. Functionally, DHA is heavily involved in retinal and brain processes. Lack of DHA predisposes for neuron dysfunction and stress in various ways, of which some is discussed here, and not of which are all understood. Because DHA and EPA are omega-3 fatty acids, their occurrence in the body relies on dietary intake from fish, crustaceans or other animals, or, to a poorer extent, synthesis from dietary alpha-linolenic acid from plants. DHA is found in greatest amounts in cold-water fatty fish.
The last decade of research has revealed a strong association between DHA and AD. For example, one of the first studies to suggest a role of fish oil and cognitive decline was an observational, prospective study at Rush’s Institute for Healthy Aging. They found elderly subjects who ate fish at least once a week had 60 percent less risk of AD (Morris et al., 2003). Observational and clinical trials on DHA have yet to show benefit in reducing existing AD. According to a systemic review of 11 observational studies and four small clinical trials—of which most only used cognitive decline as an outcome—did not find convincing evidence for prevention or treatment of AD, only that fish-derived omega-3 fatty acids slowed cognitive decline in those without dementia (Fotuhi, Mohassel, & Yaffe, 2009). As a complementary therapy, however, omega-3 fatty acid biochemical nature (especially DHA) should not go ignored. In one large cohort in France involving three cities in 1999-2000, for example, it was found that omega-6 fatty acid intake that was not also met with omega-3 fatty acid intake increased risk of dementia and AD while a diet rich in omega-3 fatty acids from fish, and fruits and vegetables reduced risk of AD, particularly in ApoE4-genotype subjects (Barberger-Gateau et al., 2007). While dieting and exercise may still play the majority role in prevention, DHA’s biochemical implications suggest that there should be continued search for the right dosages of DHA for complementary AD preventive therapy.
DHA and Insulin Sensitivity
DHA as a polyunsaturated fat (PUFA) does not adversely affect insulin sensitivity. Unlike saturated and trans fats, PUFAs are not associated with insulin resistance. Research relating to PUFAs led to a commentary in J Am Diet Assoc recommending displacement of saturated fats with PUFAS, specifically 1 to 2 g of fish-derived omega-3-PUFAs, because of reports of lower glucose intolerance along with lower blood pressure, reduced triglyceride levels, and improved endothelial function (Nettleton & Katz, 2005). The mechanisms are various. PUFAs, particularly DHA and EPA, are thought to improve insulin sensitivity by more than one pathway. The mechanisms are beyond glycemic control (Kuda et al., 2009). In adipose tissue and the liver, PUFAs influence gene transcription to increase amount of proliferator-activated receptors, sterol regulatory element-binding proteins and liver X receptors (Al-Hasani & Joost, 2005). The greater presence of these proteins and receptors result in more sensitivity to various nutrients and insulin. PUFAs also improve lipid metabolism improving prevention of obesity an diabetes. Adipose tissue secretion of adipokines decreases improve insulin sensitivity. PUFAs stimulate mitochondrial beta-oxidation, thereby promoting reduced adiposity (Flachs, Rossmeisl, Bryhn, & Kopecky, 2009). The effects are independent of PUFAs role in eicosanoid synthesis. DHA, in particular, induces lipolysis while reducing lipogenesis in what appear to be various biochemical pathways in the liver and adipocytes. PUFAs regulate gene transcription of lipogenic enzymes—such as glucose-6 phosphate dehydrogenase and fatty acid synthase—and desaturatases—such as stearoyl-C desaturase (Riserus, 2008). DHA is thought to increase lipolytic gene expression and suppressing lipogenic gene expression (Wang et al., 2009). DHA enhances expression of serum amyloid A protein, involved in lipid metabolism, and increases lipases (Wang et al., 2009). All of these are biochemical changes effective for reducing adiposity, subsequent secretions, and the factors leading to insulin resistance.
DHA also improves insulin sensitivity through docosanoid pathways. DHA and EPA immunomodulatory effects are well-known because they inhibit pro-inflammatory cytokine production (Sijben & Calder, 2007). Apart from this role, they increase formation of EPA-derived eicosanoids and DHA-derived docosanoids, resolvins and protectins (Gonzalez-Periz et al., 2009; Pauwels, Volterrani, Mariani, & Kairemo, 2009). The resolvins and protectins then help guard against inflammation as well as insulin resistance. These effects all naturally lead to decreased hyperglycemia, hyperinsulinemia and resulting hypertension.
DHA Lowers Risk of Hypertension
Blood pressure levels are lowered by DHA in various ways. Reduced insulin reduces salt reabsorption in the kidney stemming hypertension. PUFAs such as DHA guard against hypertriacylglycerolemia associated with hypertension (Viljoen & Wierzbicki, 2009). DHA also may help to regulate aldosterone and corticosterone levels associated with hypertension (Engler et al., 1999). A dose of 5 g found to lower blood pressure (Dusing, 1989). In higher amounts (50g), fish oil quite effectively reduces diastolic blood pressure, lowers triglycerides and increases bleeding time, as shown in a six-week randomized, double-blind, parallel-group study on patients with mild hypertension (Levinson, Iosiphidis, Saritelli, Herbert, & Steiner, 1990). Without hypertension to attenuate oxidative stress in the brain, damage in AD may be reduced, but studies are unclear if omega-3 fatty acids would compensate for hyperinsulinemia-induced hypertension.
DHA can also protection against cardiogenic dementia, which can affect AD. Metabolic syndrome factors leading to atherosclerosis and possible thrombosis can result in major cardiac events. DHA improvement of endothelial function, its anti-inflammatory effects from adipokine andiponectin, its inhibition of tumor necrosis factor-alpha protect against factors, and blood platelet effects help protect against heart failure and myocardial infarction (Duda et al., 2009). Heart failure and myocardial infarction can cause cardiogenic dementia, which is a heavy burden on AD patients.
DHA Guards Against Inflammation and Oxidative Stress in the Brain
Depletion of DHA in older adults leads to greater oxidative stress in the brain. Older adults who have not consistently had DHA dietary intake slowly progress to DHA depletion. The depletion leaves membrane phospholipids at greatest risk for oxidative stress insults (Lukiw & Bazan, 2006). DHA-derived neuroprotectins have direct effects on oxidative stress. Because DHA is also involved directly in neuron-to-neuron signaling and in synaptic terminals, depletion and oxidative stress directly affects learning and memory (Lukiw & Bazan, 2006). Its involvement in brain and retinal function is combined with anti-inflammatory effects reducing oxidative damage to brain and retinal cells; thus, DHA may prevent brain damage through antioxidant properties (Farooqui, Horrocks, & Farooqui, 2007). Inhibition of inflammation and oxidative stress as well as antioxidant effects suggest a dual role of DHA protection. DHA antiflammatory properties act via anti-apoptotic and neurotrophic pathways (Orr & Bazinet, 2008).
The omega-3 fatty acid mechanisms are through DHA-derived resolvins, protectins, and neuroprotectins. Each act against the three greatest brain insults occurring in AD: neuroinflammation, oxidative stress and neuron apoptic death (Farooqui, Ong, Horrocks, Chen, & Farooqui, 2007; Farooqui et al., 2007). The effects of DHA depletion is highlighted in animals, which leads to learning and memory deficits with noticeable damage to neurons and synaptic defts; levels of cognitive function are somewhat corrected after DHA supplementation (Farooqui, Horrocks, & Farooqui, 2007). As noted earlier, humans must include DHA in the diet to effectively guard against depletion. DHA-derived neuroprotectin D1 (NPD1) offers main protection against oxidative stress. Along with sphingosine 1-phosphate, DHA inhibits cytokine-mediated cyclooxygenase-2 expression (Farooqui et al., 2007). Cyclooxygenase-2 is an enzyme that produces eicosanoids in the brain. NDP1 also triggers further neuroprotectins and gene-encoding for anti-apoptic proteins (Lukiw & Bazan, 2006). These new findings all point to preservation of DHA amounts during aging.
DHA Guards Against Abeta
DHA-derived protectins protect against Abeta formation and neurotoxicity. NDP1 protects against both. NDP1 synthesis is enhanced by Abeta occurrence. The production of NDP1 is stimulated through activation of growth factors and neurotrophins in the brain, a process that is affected directly by DHA deficits (Lukiw & Bazan, 2008). NDP1 is enhanced especially at times of oxidative stress and the lower the DHA levels, the lower the levels of NDP1 production (Lukiw & Bazan, 2008). NDP1’s effects on Abeta include regulatory interaction with gene-encoding for beta-amyloid precursor protein and Abeta formation. The reduced production of Abeta delays
AD progression by allowing more Abeta to be cleared.
NDP1 inhibits formation of Abeta, thereby against aggregation. NDP1 also displays anti-amyloidogenic effects and suppression of Abeta aggregation significantly in Abeta-infused AD-model rats (Hashimoto et al., 2008). In this way, NDP1 protects against against neurotoxicity and, in the retina, against retinal damage from aggregation and glycation from diabetes (Bazan, 2009). Protection of Abeta would be secondary benefits after DHA’s support for improving insulin sensitivity.
DHA Reduces Tangles and AGEs
DHA inhibits formation of neurofibrillary tangles. Two mechanisms are involved apart from improving helping to reduce risk of elevated insulin. Indirectly, DHA inhibition of Abeta formation reduces hyperphosphorylation. Abeta induces hyperphosphorylation by kinases, which lead to the production of the paired helical filaments that end up in tangles (Cole, Ma, & Frautschy, 2009). The second mechanism is by inhibiting hyperphosphorylation directly. DHA inhibits the enzyme c-Jun N-terminal kinase that leads to tau hyperphosphorylation (Ma et al., 2009). The inhibition of the kinases help keep in check hyperphosphorylation and help correct abnormal insulin signaling. In prolonged hyperinsulinemia, this may offer important protection to brain cells.
DHA antioxidant properties make an impact in suppressing AGE and cross-linking formation. Just as other antioxidants, DHA reduces susceptibility to free radicals. The reduced susceptibility to formation of AGEs while in presence of diabetes and hyperglycemia has been demonstrated in rats (El-seweidy, El-Swefy, Ameen, & Hashem, 2002). According to studies, the suppression of neurofibrillary tangles and AGEs cross-linking by DHA may be even more effective when used with other antioxidants from fruits and vegetables (Cole et al., 2009; Ono & Yamada, 2006). By reducing glycation, DHA suppresses AGEs cross-linking of neurofibrillary tangles and Abeta aggregation as well as inhibition of enzyme pathways. The stemming of Maillard reactions and production of free radicals contributes to less oxidative stress. Reduced glyoxal levels inhibit binding to superoxide dismutase, thereby increasing antioxidant protection. The cascade of benefits suggest DHA intake and suppression of AGEs may improve of protecting neurons from progression to dysfunction and death in AD. DHA Should Be Used
Complementary Therapy in AD
DHA has various biochemical implications that all assist in guarding against factors that lead to risk of AD. Its mechanisms involve docosanoid pathways and genetic expression that lead to reducing adiposity and secretions and improvement of insulin sensitivity. Increased insulin sensitivity helps to guard against hyperinsulinemia, hyperglycemia and hypertension, which lead to abnormal insulin signaling, glycation and oxidative stress, respectively. DHA also directly guards against AD progression through inhibition of formation of Abeta. Reduced Abeta combined with improved insulin sensitivity can lead to greater Abeta degradation from IDE and greater Abeta clearance from the brain across the blood-brain barrier. DHA also inhibits neurofibrillary tangles through suppression of Abeta formation and by modulation of tau phosphorylation. Lastly, DHA antiflammatory and antioxidant effects in the brain reduce glycation, inhibit oxidative stress from glycation and reduce advanced glycation end-product cross-linking. All of these effects support DHA’s role in assisting prevention of AD.In light of epidemiological studies and clinical trials, dieting and exercise combined with DHA should be used in the therapy of obese-diabetes patients, especially those of apoE4-genotype. The most recent of reports suggest patients adhere to a Mediterranean diet (with fish at least once a week) along with daily exercise such as walking (Scarmeas et al., 2009; Scarmeas, Luchsinger, Mayeux, & Stern, 2007). A symposium in 2008 announced the first-ever preventive trial using multi-domain interventions of which results will be available in 2013. The Multidomain Alzheimer Preventive Trial (MAPT) will examine effects of fish-derived omega-3 fatty acids in AD in a three-year, randomized, controlled study conducted in hospitals of four French cities (Gillette-Guyonnet et al., 2009). Four groups of 300 elderly subjects with specific criteria of memory complaints, slow walking speed and one instrumental activity of daily living, will be given either omega-3 fatty acid supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or a placebo (Gillette-Guyonnet et al., 2009). The trial will enlighten omega-3 fatty acid research further. However, more clinical studies are needed to determine effects of omega-3 fatty acids, specifically DHA, on apoE4-genotype obese-diabetic patients who are at highest risk of developing AD. DHA’s biochemical nature presents strong evidence that it will affect the elderly subjects and apoE4-genotype obese-diabetic patients positively.
Reference List
Al-Hasani, H. & Joost, H. G. (2005). Nutrition-/diet-induced changes in gene expression in white adipose tissue. Best.Pract.Res.Clin Endocrinol.Metab, 19, 589-603.
Barberger-Gateau, P., Raffaitin, C., Letenneur, L., Berr, C., Tzourio, C., Dartigues, J. F. et al. (2007). Dietary patterns and risk of dementia: the Three-City cohort study. Neurology, 69, 1921-1930.
Bazan, N. G. (2009). Neuroprotectin D1-mediated anti-inflammatory and survival signaling in stroke, retinal degenerations, and Alzheimer's disease. J Lipid Res., 50 Suppl, S400-S405.
Carr, D. B., Goate, A., Phil, D., & Morris, J. C. (1997). Current concepts in the pathogenesis of Alzheimer's disease. Am J Med., 103, 3S-10S.
Cole, G. M., Ma, Q. L., & Frautschy, S. A. (2009). Omega-3 fatty acids and dementia. Prostaglandins Leukot.Essent.Fatty Acids.
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B. et al. (2008). apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest, 118, 4002-4013.
Du, J., Chang, J., Guo, S., Zhang, Q., & Wang, Z. (2009). ApoE 4 reduces the expression of Abeta degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons. Neurosci.Lett..
Duda, M. K., O'Shea, K. M., Tintinu, A., Xu, W., Khairallah, R. J., Barrows, B. R. et al. (2009). Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc.Res., 81, 319-327.Dusing, R. (1989). [Hemodynamic effect of unsaturated fatty acids. Do fish oils have an antihypertensive effect?]. Fortschr.Med., 107, 701-704.
El-seweidy, M. M., El-Swefy, S. E., Ameen, R. S., & Hashem, R. M. (2002). Effect of age receptor blocker and/or anti-inflammatory coadministration in relation to glycation, oxidative stress and cytokine production in stz diabetic rats. Pharmacol.Res., 45, 391-398.
Engler, M. M., Engler, M. B., Goodfriend, T. L., Ball, D. L., Yu, Z., Su, P. et al. (1999). Docosahexaenoic acid is an antihypertensive nutrient that affects aldosterone production in SHR. Proc.Soc.Exp.Biol.Med., 221, 32-38.
Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2007). Interactions between neural membrane glycerophospholipid and sphingolipid mediators: a recipe for neural cell survival or suicide. J Neurosci.Res., 85, 1834-1850.
Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2007). Modulation of inflammation in brain: a matter of fat. J Neurochem., 101, 577-599.
Farooqui, A. A., Ong, W. Y., Horrocks, L. A., Chen, P., & Farooqui, T. (2007). Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res.Rev., 56, 443-471.
Flachs, P., Rossmeisl, M., Bryhn, M., & Kopecky, J. (2009). Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci.(Lond), 116, 1-16.
Fotuhi, M., Mohassel, P., & Yaffe, K. (2009). Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat.Clin Pract.Neurol., 5, 140-152.
Freude, S., Plum, L., Schnitker, J., Leeser, U., Udelhoven, M., Krone, W. et al. (2005). Peripheral hyperinsulinemia promotes tau phosphorylation in vivo. Diabetes, 54, 3343-3348.Gil, A. & Bengmark, S. (2007). [Advanced glycation and lipoxidation end products--amplifiers of inflammation: the role of food]. Nutr Hosp., 22, 625-640.
Gillette-Guyonnet, S., Andrieu, S., Dantoine, T., Dartigues, J. F., Touchon, J., & Vellas, B. (2009). Commentary on "A roadmap for the prevention of dementia II. Leon Thal Symposium 2008." The Multidomain Alzheimer Preventive Trial (MAPT): a new approach to the prevention of Alzheimer's disease. Alzheimers.Dement., 5, 114-121.
Gonzalez-Periz, A., Horrillo, R., Ferre, N., Gronert, K., Dong, B., Moran-Salvador, E. et al. (2009). Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J, 23, 1946-1957.
Hashimoto, M., Shahdat, H. M., Yamashita, S., Katakura, M., Tanabe, Y., Fujiwara, H. et al. (2008). Docosahexaenoic acid disrupts in vitro amyloid beta(1-40) fibrillation and concomitantly inhibits amyloid levels in cerebral cortex of Alzheimer's disease model rats. J Neurochem., 107, 1634-1646.
He, X., Cooley, K., Chung, C. H., Dashti, N., & Tang, J. (2007). Apolipoprotein receptor 2 and X11 alpha/beta mediate apolipoprotein E-induced endocytosis of amyloid-beta precursor protein and beta-secretase, leading to amyloid-beta production. J Neurosci., 27, 4052-4060.
Jabeen, R., Saleemuddin, M., Petersen, J., & Mohammad, A. (2007). Inactivation and modification of superoxide dismutase by glyoxal: prevention by antibodies. Biochimie, 89, 311-318.
Kikuchi, S., Shinpo, K., Takeuchi, M., Yamagishi, S., Makita, Z., Sasaki, N. et al. (2003). Glycation--a sweet tempter for neuronal death. Brain Res.Brain Res.Rev., 41, 306-323.
Kuda, O., Jelenik, T., Jilkova, Z., Flachs, P., Rossmeisl, M., Hensler, M. et al. (2009). n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia, 52, 941-951.
Kuhla, B., Luth, H. J., Haferburg, D., Boeck, K., Arendt, T., & Munch, G. (2005). Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease. Ann.N.Y.Acad.Sci., 1043, 211-216.
Levinson, P. D., Iosiphidis, A. H., Saritelli, A. L., Herbert, P. N., & Steiner, M. (1990). Effects of n-3 fatty acids in essential hypertension. Am J Hypertens., 3, 754-760.
Luchsinger, J. A. & Gustafson, D. R. (2009). Adiposity and Alzheimer's disease. Curr.Opin.Clin Nutr Metab Care, 12, 15-21.
Luchsinger, J. A., Tang, M. X., Shea, S., & Mayeux, R. (2004). Hyperinsulinemia and risk of Alzheimer disease. Neurology, 63, 1187-1192.
Lukiw, W. J. & Bazan, N. G. (2006). Survival signalling in Alzheimer's disease. Biochem.Soc.Trans., 34, 1277-1282.
Lukiw, W. J. & Bazan, N. G. (2008). Docosahexaenoic acid and the aging brain. J Nutr, 138, 2510-2514.
Ma, Q. L., Yang, F., Rosario, E. R., Ubeda, O. J., Beech, W., Gant, D. J. et al. (2009). Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci., 29, 9078-9089.Martin, C. M. (2008). Omega-3 fatty acids: proven benefit or just a "fish story"? Consult Pharm., 23, 210-221.
Martins, C. A., Oulhaj, A., de Jager, C. A., & Williams, J. H. (2005). APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model. Neurology, 65, 1888-1893.
Morris, M. C., Evans, D. A., Bienias, J. L., Tangney, C. C., Bennett, D. A., Wilson, R. S. et al. (2003). Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch.Neurol., 60, 940-946.
Nettleton, J. A. & Katz, R. (2005). n-3 long-chain polyunsaturated fatty acids in type 2 diabetes: a review. J Am Diet.Assoc., 105, 428-440.
Ono, K. & Yamada, M. (2006). Antioxidant compounds have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. J Neurochem., 97, 105-115.
Orr, S. K. & Bazinet, R. P. (2008). The emerging role of docosahexaenoic acid in neuroinflammation. Curr.Opin.Investig.Drugs, 9, 735-743.
Pasinetti, G. M., Zhao, Z., Qin, W., Ho, L., Shrishailam, Y., Macgrogan, D. et al. (2007). Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications. Interdiscip.Top.Gerontol., 35, 159-175.
Pauwels, E. K., Volterrani, D., Mariani, G., & Kairemo, K. (2009). Fatty acid facts, Part IV: Docosahexaenoic acid and Alzheimer's disease. A story of mice, men and fish. Drug News Perspect., 22, 205-213.
Posner, H. B., Tang, M. X., Luchsinger, J., Lantigua, R., Stern, Y., & Mayeux, R. (2002). The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology, 58, 1175-1181.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Razay, G., Vreugdenhil, A., & Wilcock, G. (2006). Obesity, abdominal obesity and Alzheimer disease. Dement.Geriatr.Cogn Disord., 22, 173-176.
Riserus, U. (2008). Fatty acids and insulin sensitivity. Curr.Opin.Clin Nutr Metab Care, 11, 100-105.
Ritz, E. (2008). Metabolic syndrome and kidney disease. Blood Purif., 26, 59-62.
Salihu, H. M., Bonnema, S. M., & Alio, A. P. (2009). Obesity: What is an elderly population growing into? Maturitas, 63, 7-12.
Sasaki, N., Fukatsu, R., Tsuzuki, K., Hayashi, Y., Yoshida, T., Fujii, N. et al. (1998). Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol., 153, 1149-1155.
Sato, T., Shimogaito, N., Wu, X., Kikuchi, S., Yamagishi, S., & Takeuchi, M. (2006). Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. Am J Alzheimers.Dis.Other Demen., 21, 197-208.
Scarmeas, N., Brandt, J., Albert, M., Devanand, D. P., Marder, K., Bell, K. et al. (2002). Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease. Neurology, 58, 1182-1188.
Scarmeas, N., Luchsinger, J. A., Mayeux, R., & Stern, Y. (2007). Mediterranean diet and Alzheimer disease mortality. Neurology, 69, 1084-1093.
Scarmeas, N., Stern, Y., Mayeux, R., Manly, J. J., Schupf, N., & Luchsinger, J. A. (2009). Mediterranean diet and mild cognitive impairment. Arch.Neurol., 66, 216-225.
Schubert, M., Gautam, D., Surjo, D., Ueki, K., Baudler, S., Schubert, D. et al. (2004). Role for neuronal insulin resistance in neurodegenerative diseases. Proc.Natl.Acad.Sci.U.S.A, 101, 3100-3105.
Sijben, J. W. & Calder, P. C. (2007). Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease. Proc.Nutr Soc., 66, 237-259.
Skoog, I. (1997). The relationship between blood pressure and dementia: a review. Biomed.Pharmacother., 51, 367-375.
Viljoen, A. & Wierzbicki, A. S. (2009). Potential options to treat hypertriglyceridaemia. Curr.Drug Targets., 10, 356-362.
Wang, Y. C., Kuo, W. H., Chen, C. Y., Lin, H. Y., Wu, H. T., Liu, B. H. et al. (2009). Docosahexaenoic acid regulates serum amyloid A protein to promote lipolysis through down regulation of perilipin. J Nutr Biochem.
Yan, S. D., Yan, S. F., Chen, X., Fu, J., Chen, M., Kuppusamy, P. et al. (1995). Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide. Nat.Med., 1, 693-699.
