The gastrointestinal (GI) tract is essentially a system of muscular tubes that propel materials along its length, to enable the absorption of nutrients and the excretion of waste products. The wall of the GI tract is sealed by a layer of intestinal epithelial cells. As well as selectively absorbing nutrients and excreting waste products, the GI wall acts as a first line of defense by preventing potentially harmful toxins or bacteria in the gut from entering the blood. Certain conditions and treatments may damage the GI tract, resulting in loss of integrity of the GI wall. Known as intestinal permeability
Alzheimer’s disease (AD) is an advanced stage of dementia which progressively worsens with time and is associated with a high degree of mortality. The disease is not part of normal aging, and is likely caused by various processes that damage nerve cells. Many clinical symptoms are associated with AD, including cognitive decline, memory loss, disorientation, language impairment and so on plus AD also has a pronounced effect on the family or their caregivers. In 2010 in the US alone there were over five million cases and over twenty million worldwide.
The cause of AD is not fully known but there is increasing support that amyloid plaque much like the cholesterol laden plaque seen in the arteries around the heart also builds up in the blood vessels in the brain. There are two schools of thought regarding AD causation. The first group believe a small peptide fraction between 40 and 42 amino acids long called amyloid-beta peptide (ABP), which is thought to be the major component of the amyloid plaque eventually forms aggregates outside the cells, adherents of this group are called the Baptists (from the beta). The second group believe in a different culprit called tau proteins which undergo chemical change called phosphorylation to form tangles within the nerve cells, these scientists are referred to a Toaists (from the tau). Whatever, the cause it is becoming increasingly clear that cardiovascular risk factors like high blood pressure, high cholesterol, obesity and diabetes which collectively are the hallmark of metabolic syndrome are intimately associated with AD. All these risk factors ultimately cause endothelial damage in the blood vessels in the brain and endothelial damage is strongly associated with AD.
But what causes either plaque and/or tangles to form in the first place?
Essentially, researchers have pieced together the following sequences of amyloid plaque formation. Nerve cells continually produce large amounts of long strands of a protein called APP (amyloid precursor protein). In AD the production of this protein is significantly accelerated and much more is produced than in normal brain cells. APP is then “cut” into smaller pieces or peptide fragments including ABP by various enzymes called secretases. The small ABP units clump together due to their “glue” like properties to form larger aggregates and “stick” together around the nerve cells literally “choking” the cell to death. The body of course has a system to breakdown and clear these aggregates from the brain tissue however, in AD patients production of plaque exceeds clearance.
ABP is a nasty toxic molecule that not only directly kills nerve cells but also produces excessive amounts of free radicals which cause further damage and may assist ABP formation in a vicious cycle. Free radicals themselves cause much harm as they are quite damaging to nerve cell structures but also cause endothelial cell damage in the blood vessels.
Endothelial cells are one of the major sites of nitric oxide (NO) production. NO is one of the most important signalling molecules in the body which affects virtually every organ in the body allowing effective communication between cells and providing a wide-array of health benefits. It is a protective molecule that maintains immune, cardiovascular, nervous, kidney, stomach and intestinal, skin and other beneficial effects.
Lack of NO production by endothelial cells due to too much ABP aggregate formation and/or free radical generation only contributes to pathology of AD. Researchers have argued that if the NO production could be assured then AD would be significantly halted in its track. To test this hypothesis, researchers at the Mayo Clinic looked into the link between NO and AD through a number of elegant experiments and came to the following conclusions:
- When NO production is inhibited by using a known inhibitor, there was increased endothelial damage with ABP levels rising as expected accompanied by AD
- When NO production was increased by use of a known stimulator of NO production in an animal model of AD, the levels of ABP decreased and there was a significant improvement in memory of animals.
- Using genetic mice that cannot produce NO, the ABP levels rose in the brain tissue and there was significant brain damage compared to those mice that could naturally produce NO and were clear of AD
- NO seems to affect the production of ABP but does not affect its clearance suggesting that NO donors may work as preventative of AD rather than reversing AD.
These findings provide further support that keeping NO levels optimal may be beneficial strategy for prevention of AD and that NO donors like the inorganic nitrates may be useful.
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Austin S.A et-al “Endothelial Nitric Oxide modulates expression and processing of amyloid precursor protein” Circ. Res. 2010; 107:1498-1502