A recent Marine Drugs journal study discusses the anti-neurodegenerative effects of docosahexaenoic acid (DHA) and DHA-rich phospholipids (DH-PL) derived from fisheries and aquaculture byproducts, with a particular focus on how these components may assist in the treatment of Alzheimer's disease (AD).
Study: Marine Sources of DHA-Rich Phospholipids with Anti-Alzheimer Effect. Image Credit: Mironov Vladimir / Shutterstock.com
What is DHA?
DHA is an omega-3 long-chain polyunsaturated fatty acid (PUFA) that is a fundamental structural component of the human brain, retina, cerebral cortex, and skin. DHA is the most abundant omega-3 fatty acid found in the gray matter of the brain and retina and accounts for approximately 30% and 90% of all n-3 PUFAs in the brain and retina, respectively.
The n-3 PUFAs are lipid components that can exist as triacylglycerols, phospholipids, free fatty acids (FFAs), and cholesterol esters (CEs). These PUFAs are categorized according to their number of carbon atoms and the number and position of unsaturated bonds. These compounds have a crucial function in the architecture of cell membranes, transit of cholesterol, and energy storage.
DHA has a vital role in supporting the development of the brain and eyes in newborns, as well as preventing preterm delivery, tumors, some malignancies, inflammatory processes, and cardiovascular disease. The cardioprotective properties of DHA are attributed to its ability to alter lipid metabolism, vascular function, and membrane dynamics, as well as its anti-inflammatory and antioxidant effects.
There are two ways to synthesize DHA, endogenously from alpha-linolenic acid (ALA) or exogenously from marine sources, including fish oils, krill oils, mollusks, or algae.
How does the human body synthesize DHA?
Endogenous DHA synthesis occurs primarily in the liver, which produces the enzymes elongase and desaturase. Within the endoplasmic reticulum (ER), Δ6-desaturase converts ALA into stearidonic acid, which is desaturated by 5-desaturase to produce eicosapentaenoic acid (EPA).
A low level of DHA in the brain has been linked to various neurological disorders, including AD and Parkinson's disease. Thus, it is imperative that n3-PUFAs be incorporated into the human diet, as endogenous synthesis is inefficient and declines with age. Furthermore, previous studies have suggested that an increase in the consumption of DHA reduces the risk of AD and delays the onset of the symptoms.
What is AD?
AD is a progressive, irreversible, and complicated disease. Around 50 million people worldwide suffer from dementia, with AD accounting for 50-75% of these cases.
By 2050, the prevalence of dementia and AD will likely increase two-fold in Europe and three-fold globally, reaching up to 113 million people. The onset of AD is generally believed to begin at the age of 20 years, which is long before symptoms appear.
A wide range of symptoms is associated with AD, including gradual memory loss, language difficulties, orientation issues, problems with visuospatial skills, behavioral problems, cholinergic function changes, inability to accomplish routine tasks, and as end-stage dementia.
Pathogenesis of AD
AD arises due to the formation of extracellular peptides that produce β-amyloid plaques and tau neurofibrillary tangles (NFTs), both of which contribute to brain atrophy.
β-amyloid plaques, for example, can interfere with inter-neuronal communication at synapses, thereby contributing to neurodegeneration that can lead to neuronal damage or death.
Conversely, abnormal chemical changes cause tau to detach from microtubules and form threads that are eventually entangled to form NFTs inside neurons. These tangles block a neuron's transport system, thus impairing synaptic communication. In addition, the presence of toxic amyloid and tau phosphorylated proteins results in brain atrophy.
Causes of AD
AD is primarily caused by aging and genetics, with women more likely to develop the disease than men. Genetically, the presence of the ApoE-4 allele increases the likelihood of developing AD, as these alleles contribute to the accumulation of the β-amyloid peptide.
The development of AD can also be influenced by family factors, age, and genetics. For example, the risk of developing AD increases among individuals with a first-degree relative suffering from the disease. AD symptoms can also be exacerbated by smoking, obesity, and diabetes.
Appropriate high-density lipoprotein cholesterol (HDL) levels optimize neurological function and are essential for synapse maintenance. Meanwhile, high cholesterol levels can increase the risk for AD.
Treatments for AD
There is a decrease in acetylcholine levels in the brains of AD patients, which may be attributed to an increased concentration of cholinesterases that break down acetylcholine in the brain.
A blockade of these enzymes results in more acetylcholine being available for transmission amongst brain cells. Thus, a cholinesterase inhibitor is the first-line treatment for AD and appears to ameliorate mild to moderate cognitive and functional symptoms effectively.
Donepezil, rivastigmine, and galantamine all inhibit acetylcholinesterase; however, these drugs are associated with various side effects, such as dizziness, headache, and confusion. Furthermore, these agents only provide temporary symptoms and pain relief. As a result, these drugs cannot be called disease modifiers and cannot reverse or delay AD progression.
The N-methyl-D-aspartate (NMDA) receptor antagonist protects against neurotoxicity by preventing the consequences of high glutamate levels. Memantine, a partial NMDA receptor antagonist, and its combination with donepezil, has been approved for the treatment of moderate-to-severe AD by the United States Food and Drug Administration (FDA).
Aducanumab, a novel medication with disease-modifying potential, is a monoclonal antibody that binds to β-amyloid amino acids, thereby reducing the production of β-amyloid plaques in the AD brain.
Natural-marine-derived DHA and AD
Biologically active marine chemicals exhibit chemical characteristics that cannot be found in terrestrial products. Generally, phospholipids obtained from marine species are recommended for use in the food, pharmaceutical, and cosmetic industries due to their amphiphilic nature.
The structural diversity of neuroprotective marine chemicals includes polysaccharides, glycosaminoglycans, glycoproteins, lipids and glycolipids, and pigments. In addition, corals, sponges, algae, tunicates, and marine bacteria are some marine organisms that produce secondary metabolites.
The consumption of fish is also associated with a reduced incidence of AD. Various fish species, including mackerel, tuna, and sardines, are abundant in n-3 PUFAs, particularly (DHA)
Mechanism of DHA in treating AD
DHA-PL-rich diets stimulate the release of acetylcholine, restore cholinergic activity, maintain healthy PUFA levels, and prevent hippocampus degeneration caused by aging. Furthermore, DHA-PL may help inhibit tau phosphorylation, thus reducing neuroinflammation.
The neuroprotective effects of DHA-enriched phosphatidylcholine (DHA-PC) and DHA-enriched phosphatidylserine (DHA-PS) have been observed in old rats suffering from dementia. The hippocampus can be protected from oxidative stress and mitochondrial damage. Additionally, DHA-PS contributes to the development of insoluble β-amyloid in AD.
Marine sources of DHA
Salmon, chub mackerel, Atlantic herring, boarfish, and sardines harbor surplus DHA-PLs. Importantly, the composition and concentration of DHA-PL vary depending on the growing environment, nutrition, and pressure of the organism. A rich source of bioactive chemicals can also be found in the non-edible sections of crustaceans.
Heads, blood, viscera, skin, and tails are among the most significant marine byproducts and contain high levels of lipids, proteins, minerals, and vitamins. Recently, marine byproducts have become one of the most sought-after sources of DHA-PLs, as their utilization reduces potential concerns regarding the generation of waste and environmental sustenance.
There are a variety of methods available for the extraction of PLs, including organic solvents, atmospheric oxygen, high temperatures, and supercritical carbon dioxide (SC-CO2). SC-CO2 extraction is the most efficient method, as it produces a higher quality product, is ecologically benign, has greater purity and yield, and has a shorter extraction time than other methods.
- Ferreira, I., Rauter, A. P., & Bandarra, N. M. (2022). Marine Sources of DHA-Rich Phospholipids with Anti-Alzheimer Effect. Marine Drugs. doi:10.3390/md20110662.