HMG-CoA Reductase Inhibitors and Alzheimer's Disease: Part XXIII

HMG-CoA Reductase Inhibitors and Alzheimer's Disease:-Part XXIII

(6/1/03)-It is well known that the pathology of Alzheimer's disease is characterized by the progressive accumulation of intraneuronal fibrillary tangles with abnormally phosphorylated tau protein, and by amyloid peptide condensed within extracellular neuritic plaques often surrounded by proliferating activated microglia and astrocytes. Phosphorylation is a chemical reaction in which a phosphate group becomes covalently coupled to another molecule. Scientists have known for years that amyloid in the brain is formed when amyloid precursor protein (APP) is broken up. This results in the formation of amyloid protein fragments that clump together to form insoluble amyloid plaques in certain areas of the brain. It has led to attempts to interfere with the production of beta amyloid or more recently to attempts to degrade amyloid or its plaques.

However, there is no conclusive evidence indicating that amyloid plaques and neurofibrillary tangles are the cause and not a product of Alzheimer's disease. Plaques and tangles can be observed in the brains of individuals without any detectable form of dementia. (See: Snowdon DA. Aging and Alzheimer's Disease: lessons from the Nun study. Gerontologist 1997; 37(2): 150-156).

Other comprehensive causes of Alzheimer's disease have been postulated, among which is an accumulation of evidence that abnormalities in lipid metabolism plays an important role in AD. Janelle Cooper has reviewed the research in this area proposing that dietary lipids are the principle risk factor in the development of late-onset AD. Her review article in Drugs and Aging (2003; 20(6): 399-418) states: "The degree of saturation of fatty acids and the position of the first double bond in essential fatty acids are the most critical factors determining the effects of dietary fats on the risk of AD, with unsaturated fats and n-3 double bonds protection and an overabundance of saturated fats or n-double bonds increasing risk. The interaction of dietary lipids and apolipoprotein E isoforms may determine the risk and rate of sustained autoperoxidation within cellular membranes and the efficiency of membrane repair". Lipid peroxidation is an oxidative process leading to the destruction of biological membranes. It is implicated in diverse pathophysiologic conditions such as aging, atherosclerosis, rheumatic disease, cancer, cardiac and cerebral ischemias, respiratory distress syndrome, various liver diseases, sepsis, trauma, burns, and the toxicity to various organs induced by certain metals, solvents, pesticides and drugs. Apolipoprotein E is a protein that carries cholesterol in blood and that appears to play some role in brain function.

This theory does not dispute that amyloid protein and neurotubules are critical components of AD, but postulates a more upstream activity that sets up a cascade of events that culminate in AD. It also opens up an avenue of AD prevention through the use of a class of drugs called HMG-CoA reductase inhibitors. This class is probably more familiar to the general readers of the articles on this site as drugs called statins. It has led Dr. Cooper to conclude: "Intervention involving dietary lipids and lipid metabolism show great promise in slowing or possibly averting the development of AD, including dietary changes, cholesterol-modifying agents and antitoxins" leading her to propose "the possibility of the therapeutic intervention with dietary modification and lipid-lowering agents such as HMG-CoA reductase inhibitors."

For more information on this topic, beside the references mentioned above, we suggest our readers consult
1. Selkoe, D. Toward a comprehensive theory of AD. Ann NY Acad. Sci. 2000; 924:17-25
2. Practice, D et al Increased lipid peroxidation precedes amyloid plaque formation in the animal model of Alzheimer Amyloidosis. J Neurosci 2001, June; 21(12):4183-4187.

For some other articles on Alzheimer's Disease Please See:

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Harold Rubin, MS, ABD, CRC, Guest Lecturer
posted June 1, 2003

http://www.therubins.com

To e-mail: hrubin12@nyc.rr.com or rubin@brainlink.com

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