for heart disease such as diabetes, high blood pressure, a high-fat diet, elevated homocysteine levels, cigarette smoking, and a sedentary lifestyle are also factors in the development of AD (Snowdon, D., et al., 2000 and Weir and Molloy, 2000). Thus the evidence of plaque buildup, or atherosclerosis, in the teenaged years leads many researchers to speculate that AD plaque may start its gradual corrosive process that early, as well. Nutritionally, this finding indicates that a diet that is good for the heart is also good for the brain.
How is Alzheimer's Disease Identified?
Let's look at the major players of this complex brain game in order to appreciate the complicated interaction of the players that slowly overwhelm the mental and physical aspects of our being once AD has taken over. The main players are β-amyloid plaques, neurofibrillary tangles, oxidative stress, and chronic inflammation. The β-amyloid plaques are widely perceived to be the start of the problem. They are derived from the amyloid precursor protein (APP). It is a simple protein that is found in the lipid membrane that surrounds all cells. APP activities are regulated by cholesterol found in these lipid membranes (Cordy, Hooper, and Turner, 2006). Under normal cellular conditions an enzyme called α-secretase cuts the APP first, and then another enzyme γ-secretase cuts it into a soluble protein of forty amino acids (the building blocks of proteins) in length. This soluble protein called α-amyloid is harmlessly secreted from the lipid membrane into the extracellular space to perform its role in cell growth, cell-to-cell communication, and as a contributor to cellular repair (Whitbourne, S., 2002). Our dynamic metabolism is continually responding to changes and therefore the APP, with its wide range of activities, has developed an alternate enzyme to cut it. In the alternative pathway, APP is first cut by β-secretase and then by γ-secretase. This action produces a soluble protein fragment that is approximately forty-two amino acids long, called β-amyloid (Aβ). But when Aβ combines with other Aβ proteins, it becomes insoluble and sticky.
The two different pathways for APP are:
APP
Both of these proteins are normal derivatives of APP metabolism with roughly 90 percent of them being α-amyloid and 10 percent being Aβ. What role the Aβ type has is speculative at this time. It has been hypothesized that when they are still soluble, Aβ regulates brain cell growth similar to α-amyloid, but Aβ is associated with the growth at sites of injury or disease. These researchers hypothesize that as we age, factors like heart disease, diabetes, injury, a sedentary lifestyle, or most likely a combination of effects that cause the brain's metabolism to decline, produce an increase in Aβ to facilitate brain cell growth at damaged areas (Struble, R., et al., 2010).
It is also known that Aβ plaques become poisonous or toxic when they combine together or aggregate, and this combination can damage the nerve cells. This toxic aggregation might occur to signal the immune system to clear the used Aβ from the extracellular space through the activation of the macrophages and, exclusive to the brain, microglia. Both the macrophages and the microglia are considered to be the janitors of the immune system. Unfortunately, as we age these janitors may become faulty and may not adequately remove the cells’ waste products (Fiala, M., et al, 2005). Therefore, as the many risk factors of aging start accumulating and the brain's metabolism declines, the percentage of toxic, insoluble Aβ peptides increases. As these insoluble Aβ aggregates add up, they slowly become compact spherical structures in the brain called senile plaques. A wide range of research is ongoing to stop APP from ever engaging in the alternate β/γ-secretase pathway (Vassar, R., et al., 2009). But if the above hypothesis is correct, increasing the brain's metabolic activity should be the goal. Prevention and nutrition become important in order to keep our immune system healthy and our brain's metabolism active.
While these senile plaques are building up outside the brain cells (called neurons), inside the cells, even more devastating action is occurring. Insoluble neurofibrillary tangles (NFT) are forming, most likely caused by repeated internal and external neuron damage. The damage occurs by a process known as oxidative stress, slowly killing the neuron by disrupting its basic mechanisms. Where do these abnormal tangles come from? The neuronal cell structure is called the cytoskeletal system (cyto means cell), and it is made up of filaments and microtubules. These filaments and microtubules have other proteins associated with them that cross-link with them for support. Think of the filaments and microtubules as the steel beams of a large building, with the floors being the cross-linking proteins.
One of these cross-linking proteins is a prime suspect in AD. Its name is tau, and it belongs to a family of proteins appropriately called microtubule associated proteins (MAP). This whole MAP family of proteins is found throughout the body and brain as structural components of cells, including the tau protein. In a normal neuron, tau's role is to bind and support the microtubule assembly in the long branches of the neurons called axons, and to a lesser degree in the neuron's central body. The tau protein's role is extremely important because it supports the neuron's structure, which allows intracellular communication and the transport of nutrients throughout the neuron and its numerous long axons.
Unfortunately, tau may undergo dangerous biochemical modifications that result in what is called hyperphosphorylation, a change that makes tau nonfunctional. This change causes, among other things, the loss of the whole filament/microtubule assembly. All these filaments and microtubules then stick together—having lost their support—and form the insoluble NFTs. Ultimately, the whole cytoskeletal system breaks down, killing the cell. These biochemical modifications are also believed to be caused by a decrease in metabolic activity that leads to oxidative stress, which is the third member of the AD team.
The Role of Oxidative Stress
The natural mechanism of the immune system is activated when a cell is in distress or when foreign invaders are detected. This activation may be beneficial to the cell because either the distress is brought under control and any damage is repaired, or the foreign invaders are captured and eliminated. If the damage is too great, however, the immune system goes into overdrive trying to salvage the cell or group of cells. The term “positive feedback loop” means that over the years, depending on the damage or “oxidative stress,” the immune system grows out of control as it tries to repair the cells. This effort produces even more damage, which causes the immune system to send in more immune molecules, and the cycle repeats over and over again. Numerous hypotheses regard chronic oxidative stress suffered over a lifetime to be a contributing factor in Alzheimer's disease (Sultana, Perluigi, and Butterfield, 2006).
What is oxidation and oxidative stress? An oxidant is a molecule that accepts, or in the case of “free radicals,” steals an electron from another molecule. Oxygen is an oxidant that we see in action all the time. When an apple slice turns brown or butter turns rancid, it is because oxygen has interacted with their cells. When copper gets that green patina or metal turns to rust, you can thank oxygen for those changes. Oxygen is nature's way of breaking things down so that they can decompose—as in the case of rotting fruit. Yet oxygen is vital to the body and brain. The oxygen that we inhale goes from our lungs to the blood stream where it combines with glucose (or other fuels) to produce energy for the whole body, and especially the brain. Most of the time, oxygen metabolizes very efficiently within each of our cells, resulting in a balanced exchange of electrons. These interactions are termed “oxidation” (accepting electrons) and “reduction” (the loss of electrons). The interactions actually happen simultaneously and are a natural process that is necessary to keep the body healthy.
Free