1- What Are cytokines?

Cytokines are small proteins that are produced by white blood cells, such as lymphocytes T and lymphocytes B, and endothelial cells, mast cells, fibroblasts, and mesenchymal cells.

In the nervous system, cytokines are produced by microglia, astrocytes, endothelial cells, and macrophages [1].

• Lymphocytes T

Lymphocytes T are immune cells involved in the killing of viruses and cancer cells.

• Lymphocytes B

Lymphocytes B are immune cells that produce antibodies against viruses, bacteria, and cancer cells. Anomalies in the recognition of the body’s own antigens lead to autoimmune diseases.

• Endothelial Cells

Endothelial cells are the building block of vessels.

• Mesenchymal Cells

Mesenchymal Cells are cells that generate connective tissues.

• Fibroblasts

Fibroblasts are cells found in connective tissues where they produce collagen and are also involved in wound healing.

• Mast Cells

Mast cells are found in connective tissues where they produce histamine (neurotransmitter) and heparin (anticoagulant).

• Macrophages

Macrophages are a type of white cells that are responsible for engulfing and digesting viruses, microbes, cancer cells, debris of cells, and foreign substances.

• Microglia

Microglia are non-neuronal cells that are specifically found in the brain and the spinal cord where they play an essential role in the immune response.

• Astrocytes

Astrocytes are also non-neuronal cells responsible for providing nutrients to the nervous system and support the activity of the nervous system endothelial cells in forming the blood-brain barrier.

2- What Are Chemokines?

Chemokines are also cytokines that control the movement of lymphocytes in response to inflammation, infection, or cancer.

3- What Are Secondary Messengers?

When a ligand such as a growth factor, binds to a receptor on the surface of cells in the body there is a transmission of information within the cells by small molecules and ions that promote the expression of proteins necessary for the function of the cell.

4- What Are Reactive Oxygen Species (ROS)?

Reactive oxygen species (ROS) are produced by the metabolism of oxygen (O2) in the body’s cells. An excess of ROS (e.g., free radicals) can damage the DNA of the cells causing their death or mutations that can lead to cancer.

5- What Causes Neuroinflammation?

• Traumatic Brain Injury

A traumatic brain injury can be mechanical such as a blow to the brain or spinal cord leading to tissue damage, or pathological due to tissue damage caused by excitotoxicity (excessive excitation of neurotransmitters), ischemic injury, or alterations in mitochondria function [2].

• Spinal Cord Injury

A spinal injury is due to an acute or localized (focal) trauma, a reduced blood supply (ischemia), or excitotoxicity.

• Infection

The most known infection of the central nervous system (CNS) is due to Mycobacterium tuberculosis (tuberculosis), but there are other infections such as Plasmodium falciparum (malaria), Rickettsia conorii (Boutonneuse fever), Trypanosoma cruzi (Chagas disease) [3].

These infections cause inflammation by altering the function of the CNS vessels.

• Autoimmunity

Autoimmunity is due to the production of antibodies by lymphocytes B against antigens that are expressed by normal cells, including cells of the brain and spinal cord.

These antibodies are known as autoantibodies and attack the body’s cells and tissues causing their damage and inflammation.

• Toxic Metabolites

Alterations in CNS metabolites (Neurometabolites) such as N-acethylaspartate (NAA), creatine, and glutamine can cause injuries or death of neurons in the central nervous system leading to inflammation.

• Aging

Although the mechanisms are not known, there is an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines in the aged central nervous system.

6- What Are the Symptoms of Neuroinflammation?

The symptoms of neuroinflammation depend on the injured part of the central nervous and the type of injury; however, some of the common symptoms are pain, depression, and fatigue.

7- What Mechanisms Mediate Inflammation in the Brain?

The immune response and inflammation in the brain and spinal cord are mainly mediated by microglia and astrocytes but also endothelial cells, and macrophages.

The brain and spinal cord are closed environments due to the presence of the blood-brain barrier (BBB), therefore, not all the cells of the immune system can enter [4].

Following the damage of the brain or spinal cord, microglia are activated and secrete cytokines and chemokines that recruit other cell types such as astrocytes, endothelial cells, and macrophages to repair the damage.

However, during the early stage of spinal injury, there is an infiltration of other immune cells, such as neutrophils, and monocytes. Lymphocytes also contribute to inflammation at a later stage of the injury [1].

9- How Does Neuroinflammation Contribute to Neurodegeneration?

Although the mechanisms are not well known, neuroinflammation has been implicated in the pathogenesis of dementia through its role in cerebral small vessel disease (SVD)-vascular dementia [5].

Neuroinflammation contributes to multiple sclerosis through the disruption of the blood-brain barrier resulting in the recruitment of immune cells and the secretion of proinflammatory factors and antibodies against the myelin sheath.

It was suggested that neuroinflammation also contributes to Alzheimer’s disease through the incapacity of microglia to eliminate amyloid-beta plaques [6].

10- How Is Neuroinflammation Treated?

For multiple sclerosis, a monoclonal antibody (rituximab) has been successfully used to target lymphocytes B responsible for the production of antibodies against the myelin sheet.

However, this treatment has also a potential risk of inducing a rare disease known as progressive multifocal leukoencephalopathy that causes damage to the white matter in multiple parts of the brain [7].

For Alzheimer’s disease and Parkinson’s disease, there are several ongoing clinical trials using inhibitors that regulate the function of microglia and astrocytes which are involved in the pathogenesis of AD and PD [7].

Conclusion

Neuroinflammation is a natural response of the brain and spinal cord to injuries, autoimmunity, infection, toxic metabolites, and aging.

Although its role is to promote the repair of tissues’ damage, proinflammatory cytokines can also result in the recruitment of other types of cells, such as immune cells, fibroblasts, and lymphocytes that can lead to additional and indirect tissue damage resulting in neurodegenerative diseases such as dementia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

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1- What Are Omega 3 Fatty Acids?

Lipids or fats are made from saturated and unsaturated fatty acids. Omega 3 fatty acids are a type of fatty acids known as polyunsaturated fatty acids.

Omega 3 Fatty Acids are also divided into docosahexaenoic acid (DHA), linolenic acid (ALA), and eicosapentaenoic acid (EPA).

Docosahexaenoic Acid (DHA) is the principal constituent of the plasma membrane of neurons found in the brain and cerebral cortex. It is also found in the retina and skin.

Eicosapentaenoic Acid (EPA) is essential for the synthesis of the vasodilator, anticoagulant, and inflammatory hormone, Prostaglandin (PG). It is also essential critical for the synthesis of the pro-coagulation and thrombosis factor, thromboxane, and the inflammation mediators, leukotrienes.

Linolenic Acid (ALA) is involved in the regulation of blood lipids and endothelial (Vessels) function. It has also significant anti-inflammatory and anti-thrombotic effects.

2- Which Types of Omega-3 Fatty Acids Are Found in Fish?

Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA) are found in fatty fish such as salmon, tuna, herring, mackerel, sardine, and fish oils,

Linolenic Acid (ALA) is found in fish but in flaxseed, chia, walnuts, hemp, and vegetable oils.

3- Omega 3 Benefits for the Brain

Omega 3 fatty acids are present in the membrane of brain cells (neurons) and are protecting factors of the nervous system [1]. These are some of the functions of omega 3 fatty acids in the brain:

• Omega 3 Fatty Acids and Neurotransmission

Neurotransmission is the process of transmission of information between the brain and the other parts of the body.

This transmission is carried out by neurotransmitters, such as dopamine, serotonin, glutamate, GABA, along the neurons.

Neurotransmitters travel from one neuron to another through synapses; however, to do so they must be transported by membranous vesicles that are made essentially made of omega 3 fatty acids [2].

• Omega 3 Fatty Acids and Neurogenesis

Neurogenesis is a process of making neurons and other types of brain cells that begins during embryonic life and that continue in certain parts of the adult brain such as the hippocampus and the subventricular zone of the cerebral cortex.

The hippocampus is the part of the brain that is involved in memory and the subventricular zone is implicated in olfaction (sensation of smell).

Omega 3 fatty acids are necessary for the production of new hippocampal neurons and olfactory neurons as they are essential for the formation of the membranes of the new neurons.

• Omega 3 Fatty Acids and Membrane Receptor Function

Omega 3 fatty acids have been shown to regulate the activity of the adenosine A_2A and dopamine D₂ receptors that are found on neurons, and which modulate the function of the neurotransmitters, glutamate, and dopamine [3].

• Omega 3 Fatty Acids and Synaptic Plasticity

Neurotransmission is performed through the transfer of neurotransmitters from one neuron to another through synapses.

The changes in strength or weakness of the synapses are known as synaptic plasticity. These changes can regulate the number of neurotransmitter receptors that bind neurotransmitters, and therefore, control the excitation of neurons.

Omega 3 fatty acids are involved in changing the strength or efficacy of synaptic plasticity and inducing the growth of new synaptic connections [4].

• Omega 3 Fatty Acids and Neuroinflammation

Neuroinflammation is an inflammation that happens within the central nervous system (brain and spinal cord) following injury.

Omega 3 fatty acids have been shown to have anti-inflammatory properties through their involvement in the synthesis of pre-resolving mediators, such as resolvins, protectins, and maresins. These mediators are involved in the resolution of inflammation [5].

4- Omega-3 Fatty Acids and Neuropsychiatric Disorders

• Omega-3 Fatty Acids and Schizophrenia

A study found that the blood levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are significantly lower in schizophrenia patients compared to healthy control individuals.

It also found that schizophrenia patients who consume more omega 3 fatty acids have an improvement in schizophrenia symptoms [6].

• Omega-3 Fatty Acids and Mood Disorders

Mood disorders have been associated with abnormalities in the composition and concentration of omega 3 fatty acids.

Patients with major depression have significantly lower omega 3 fatty acids in the blood cells and the severity of the depression correlated with the concentration of 3 fatty acids [7] [8].

5- Omega-3 Fatty Acids and Alzheimer’s Disease (AD)

Several studies have shown a correlation between Alzheimer’s disease (AD) and the decrease in the levels of omega 3 fatty acids in the hippocampus and cortex [9][10].

However, further clinical trials are required to confirm the beneficial role of omega 3 fatty acids for patients with Alzheimer’s disease.

6- Omega-3 Fatty Acids and Attention Deficit Hyperactivity Disorder (ADHD)

Although the effect was modest, a study reported that supplementation with omega 3 fatty acids improved the symptoms of attention deficit hyperactivity disorder (ADHD) [11].

7- Omega-3 Fatty Acids and Acute Neuronal Injury

Excess or chronic neuroinflammation can cause damage and death of nerve cells. Through their neuroprotective and anti-inflammatory properties, Omega 3 fatty acids can prevent the induction of acute neuronal injury that is can be caused by neuroinflammation [12].

8- Omega-3 Fatty Acids and Traumatic Brain Injury

Traumatic brain injury can result in sensory and motor disabilities and post-traumatic inflammation that limit the regeneration of neuronal axons.

An experimental study showed a significant increase in locomotor performance and survival neurons following the administration of Omega 3 fatty acids [13].

Conclusion

Fish is rich in omega 3 fatty acids and specifically in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Omega 3 fatty acids have many roles in brain function, cognition, the generation of new neurons in the hippocampus and the cerebral cortex, and in neuroinflammation.

Omega 3 fatty acids also have neuroprotective properties that can help with the treatment of mental health disorders such as schizophrenia and major depression, Alzheimer’s disease, brain injury, ADHD, neuronal injury, and protection against neuroinflammation.

Therefore, to the question “Is It True That Fish Is Brain Food?”, the answer is an absolute, yes, and I will always have fish as part of my diet.

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This accumulation results in loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline such as memory defects.

A connection between the brain and the gastrointestinal tract has been suggested due to the significant influence of the gastrointestinal flora (microbiome or microbiota) over the brain-gut axis [1] [2].

1. What Is the Role of Gut Flora in Alzheimer’s Disease?

The gastrointestinal tract is full of harmless bacteria that positively affect our health and contribute to our body’s natural processes. However, unbalance of the gut flora (Dysbiosis) can lead to significant pathological changes that can affect our immune system and brain functions.

This unbalance is due to several reasons such as a dietary change, accidental chemical consumption (unwashed pesticides on fruit and vegetables), alcohol consumption, inflammation, and excessive antibiotics’ medication.

2- What Is the Role of Dietary Changes in Alzheimer’s disease (AD)?

To reduce the risk of losing neurons in the hippocampus and cerebral cortex, responsible for the progressive cognitive decline (memory loss), it is necessary to consume food that is rich in compounds that promote and maintain the survival of neurons and their connectivity to each other.

• Glutathione

Glutathione is an antioxidant that prevents damage to neurons that are caused by reactive oxidative stress, such as free radicals, and heavy metals.

Substances that are metabolized in the liver and excreted in the bile require conjugation with glutathione to facilitate their absorption by the gut circulation [3].

Glutathione is mainly found in foods such as beef, poultry, eggs, milk, avocados, strawberries, oranges, blueberries, watermelon, peaches, and grapefruit.

• Polyphenols

Polyphenols are organic compounds that include flavonoids, such as quercetin, and epigallocatechin gallate. Quercetin is an inhibitor of the enzyme, BACE-1 (beta-amyloid precursor protein–cleaving enzyme 1) that has a role in the formation of beta-amyloid plaques [4].

In the gut, the microbiota transforms polyphenols into neuroprotective polyphenols that protect neurons during Alzheimer’s disease [4].  

Foods that are rich in polyphenols include cocoa products, blueberries, various spices, dried herbs, flaxseed, nuts (chestnut, hazelnut), olive and artichoke heads. 

• Curcumin (Turmeric)

Curcumin is a bioactive polyphenolic extract of turmeric that is used as a spice, food additive, and herbal medicine.

Curcumin has antioxidant, anti-inflammatory, metal binding, and neuroprotective activities that improve the cognitive functions in patients with Alzheimer’s disease (AD) [5]. 

In the gut, curcumin was suggested to favor beneficial bacteria by increasing the abundance of Bifidobacterium and Lactobacilli and reducing pathogenic bacteria such as Prevotellaceae, Enterobacteria, Enterococci, and Coriobacteriia that can affect brain health [6].

• Vitamin B6

Vitamin B6 is an essential coenzyme involved in the metabolism of glucose, fat, and proteins [7]. Vitamin B6 is also involved in lowering the level of homocysteine (made from methionine) in the blood by converting it into cysteine.

An increased homocysteine level (hyperhomocysteinemia) can result in blood vessels damage, including vessels in the brain which can affect nutrients supply to neurons leading to their death by starvation [8].

In the gut, Vitamin B6 (microbial vitamin B6) can be produced by bacteria such as Bacteroidetes and Proteobacteria, where it also contributes to the gut immunity to ensure the proper function of the gut in nutrients absorption [9].

Vitamin B6 is mainly found in meat products such as Beef, pork, chicken, and fish.

• Vitamin B12

Vitamin B12 is a coenzyme involved in fatty acids and protein metabolisms, DNA synthesis, and maturation of red blood cells.

It is also necessary for the production of myelin, a protein covering neurons, and necessary for the nervous system function through its role in the transfer of nerve impulses and metabolic support of neurons [10].

Like vitamin B6, vitamin B12 also reduces homocysteine level (hyperhomocysteinemia) and prevents the damage of blood vessels, including vessels of the brain which, and therefore, can affect nutrients supply to neurons leading to their death by starvation [11].

In the gut, certain bacteria and archaea produce vitamin B12 during food fermentation.

It is naturally present in foods such as meat, liver, milk, clams, fortified breakfast cereals, and eggs.

• Folic Acid (Vitamin B9)

Vitamin B9 is required for DNA synthesis and for the activation of vitamin B12, and therefore, indirectly plays an important role in protecting blood vessels from damage, including the brain blood vessels [12].

Many bacteria in the gut produce an active form of folic acid known as tetrahydrofolate (THF), including Bacteroides, firmicutes, actinobacteria, fusobacteria, and proteobacteria.

Many types of food contain vitamin B9; however, due to its instability (e.g., high heat cooking), it is being added to several food sources as a fortifier to prevent a vitamin B9 deficiency.

• Unsaturated Fatty Acids

Unsaturated Fatty Acids are parts of phospholipids that are necessary for the formation of the membranes of cells, including neurons. One of the most known unsaturated Fatty Acids is omega-3 polyunsaturated fatty acids [13].

In the gut, the microbiota regulates the availability and absorption of unsaturated fatty acids

Foods that are rich in omega-3 polyunsaturated fatty acids include salmon, sardines, and mackerel.

• Lecithin

Lecithin is a fatty substance composed of a mixture of phospholipids that are rich in choline, a necessary component of the neurotransmitter acetylcholine that is involved in memory, mood, muscle, and nervous system functions [14].

In the gut, food that contains lecithin is digested by the pancreas and mucosal enzymes to produce choline that is absorbed by the gut circulation.

Lecithin is mainly found in foods such as meat, poultry, fish, dairy products, and eggs.

• Caffeine

Caffeine is a stimulant of the central nervous system where it has effects on learning, memory, alertness, and concentration. Caffeine has antioxidant effects and may protect against cell damage, including damages to neurons, by reducing oxidative stress [15].

Beverages, such as coffee, tea, soft and energy drinks, are digested by the gut flora to generate caffeine that is absorbed by the intestine’s circulation.

• Prebiotics

The most common prebiotics are fructooligosaccharides, galactooligosaccharides, and trans-galactooligosaccharides, but other prebiotics plays important roles in health and aging such as insulin enriched-oligofructose, lactulose, and oligofructose [16].

They are indigestible carbohydrates that are fermented and broken down by probiotics to obtain survival energy, and short-chain fatty acids such as lactic acid, butyric acid, and propionic acid.

The administration of prebiotics such as non-starch polysaccharides was shown to improve the performance of working and recognition memory and cognitive functions [17].

Prebiotics are found in carrots, quinoa, radishes, onions, chicory roots, konjac roots, oats, yams, garlic, barley, wheat bran, berries, apples, asparagus, bananas, leeks, chia seeds, flax seeds, cocoa, coconut, jicama root, and dandelion greens.

• Probiotics

The gut contains beneficial bacteria known as good bacteria, such as Lactobacillus and Bifidobacterium. These bacteria help other gut bacteria produce nutrients for the body by providing them with nutrients that are commonly known as prebiotics [18].

Probiotics are found in yogurt, lactobacillus milk, some cheeses such as Gouda, cheddar, cottage cheese, and mozzarella, pickles, sauerkraut, kefir, kimchi, tempeh, kombucha, and miso.

3- What Is the Role of Alcohol in Alzheimer’s disease (AD)?

Excessive consumption of alcohol for a long period can damage the brain and reduce the size of the brain white matter responsible for signal transmission in the brain.

It can also cause a deficiency in vitamin B1 resulting in diseases such as Korsakoff’s syndrome characterized by alterations in short-term memory [19].

4- What Is the Role of Pesticides in Alzheimer’s disease (AD)?

Pesticides are neurotoxins that can induce oxidative stress, the fibrilization of tau and alpha-synuclein (formation of amyloid fibrils), alteration in the function of mitochondria, and the loss of neurons [20].

People such as gardeners and farmers that use pesticides for their activities are at higher risks of neurodegenerative diseases such as Alzheimer’s disease (AD).

Accidental consumption of pesticides associated with unwashed pesticides on fruit and vegetables can also increase the risk of developing Alzheimer’s disease (AD).

5- What Is the Role of Excessive Antibiotic Medication in Alzheimer’s disease (AD)?

Excessive use of antibiotics can cause an imbalance in the gut flora (microbiota) and affect the function of the probiotic population necessary for the generation of essential nutrients to the function of the body organs, including the brain [21].

6- What Is the Role of Neuroinflammation in Alzheimer’s disease (AD)?

Imbalance of the gut flora (Dysbiosis) can lead to disruptions in the gastrointestinal permeability and blood-brain barrier, that are due to the secretion of amyloid and lipopolysaccharides (LPS), known to modulate the inflammatory signaling pathway leading to neuroinflammation, neuronal injury, and ultimately to neuronal death in Alzheimer’s disease (AD) [1] [22]. 

Conclusion

To reduce the risk of Alzheimer’s disease (AD) that could be associated with an unbalance in the Gut flora (Dysbiosis), a healthy diet and the implementation of a healthy nutritive plan throughout a life of an individual is necessary.

Intake of pre-and probiotics, vitamins (B-complex vitamins), calcium, magnesium, zinc, and beta-carotene, can help prevent dysbiosis, while the consumption of processed meat, high carbohydrates containing food, and dairy products as well as excessive use of antibiotics, may promote dysbiosis.

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