Alzheimer’s Disease

//Alzheimer’s Disease
Alzheimer’s Disease2018-08-27T02:10:09+00:00

ALZHEIMER’S DISEASE 

  

The etiology or cause of Alzheimer’s disease is a topic of considerable debate. It is most probably, however, a multifactorial process. So in that regard, there’s a bit of truth in everyone’s opinion. The only intelligent perspective is, of course, mine. As I have often stated, all disease processes find their origins in oxidation, inflammation, infection, or an immune system gone awry, or a combination of these. Alzheimer’s disease is no exception. However, in the brain there is an additional consideration, the function of the neurotransmitters, the chemicals secreted by one neuron or nerve cell and picked up by the receptors of the next neuron in the chain to perpetuate the electrical signal.  Excesses or deficiencies in these neurotransmitters can also cause abnormalities of thought, sensation and motor function and other disease processes. Usually, though, dysfunctions of neurotransmitters are the result of one of the “big 4” listed above. In this section we’ll review the role of several drugs and endogenous chemicals such as CoEnzyme Q10, Acetyl-L-Carnitine, neuroendocrine hormones, and Melatonin, a protective neurotransmitter, in reducing oxidation and in decreasing inflammation, all considered to be significant factors in the etiology of Alzheimer’s.

 Startling statistics on Alzheimer’s disease:

  • 4.5 million Americans suffer from Alzheimer’s disease 
  • Most family members feel that drugs are the only answer to slowing down the disease 
  • Alzheimer’s patients usually take one drug 
  • Estimated cost of each drug: $120 a month 
  • The overall costs of Americans taking the drugs are $1.2 billion a year 

There is a continuing controversy on whether the drugs currently used in Alzheimer patients really work. Some doctors are beginning to doubt their effectiveness as they observe the drugs’ effects on their patients. Recently (early 2006), there was a paper suggesting that two cups of coffee were just as effective in improving the cognitive function in these patients.  Coffee would certainly be cheaper, but $3.00 for two months of over-the-counter melatonin capsules is cheaper still.  Four of the prescription drugs (Aricept, Exelon, Reminyl and Tacrine (at roughly $3.00 per pill)) are believed to work by increasing the levels of acetylcholine, a neurotransmitter, in the brain by inhibiting its breakdown enzyme acetylcholinesterase.  As of the date of this writing, even the FDA has not found these drugs to be significantly beneficial in treating this disease to be awarded their approval but many doctors are prescribing them. In addition, there is increasing evidence that this postulated deficiency of acetylcholine is not the cause of Alzheimer’s Disease and that any decrease in the levels of this neurotransmitter does not occur until the late stages of the disease. This comes from data gathered in the Religious Orders Study that looked at the amount of choline acetyltransferase enzyme which has long been known to be the rate limiting emzyme step in the production of acetylcholine. With the information presented below and the expense of the cholinesterase inhibitors mentioned above, there are better ways of preventing and combating Alzheimer’s. 

 However, boosting the brain’s acetylcholine levels does improve performance. Nicotine patches have been shown to be effective in reversing some of the memory loss in the elderly  (White, H.K. Psychopharmacology, Online First Edition, accessed Dec. 5, 2003). This Duke University study included 11 seniors with age-associated memory impairment.  After getting nicotine — but not after getting a placebo patch — the seniors completed memory and attention tests twice as fast as they had before treatment. In addition, the seniors themselves reported improved memory after getting a nicotine boost. This makes perfect sense since nicotine will also stimulate the acetylcholine receptors in the brain.

 

Curcurmin or Curry Spice Tumeric was recently shown to be effective in reducing the protein aggregation responsible for the Beta Amyloid build up seen in the neurofibrillary tangles thought to be responsible for Alzheimer’s disease. The study published in the Journal of Biological Chemistry by Dr. Gregory Cole at UCLA reported that curcurmin actually blocked the amyloid fibers in the brains of elderly lab mice. Similar results are published in the American Journal of Epidemiology July 2006. Other studies have shown that where curry is a common dietary spice, such as India, the incidence of Alzheimer’s Disease is very low. 

 The exact mechanism for this is unclear. It may be by the inhibition of the oxidation of brain proteins into the protein carbonyls that form the beta amyloid since curcurmin is a powerful antioxidant. This is similar to at least one of the mechanisms by which melatonin prevents Alzheimer’s Disease (see below). Or it may be by its anti-inflammatory effect as it is known to decrease the inflammatory cytokine, interleukin 8, by reducing the activity of nuclear factor Kappa-B which regulates the production of interleukin 8. As an aside, at MD Anderson Cancer Center in Houston, curry has been repeatedly demonstrated to decrease the incidence of colon, breast, prostate, pancreatic, and melanoma cancers as well (Aggarwal Cancer 8/2005) and it is believed to be this regulation of NF Kappa-B protein and the resulting anti-inflammatory effect that is responsible. Remember what I said about the ‘Big 4’ oxidation, inflammation, infection, or an immune system gone awry?  Some studies recommend capsules of 500 mg, though the dosing is still to be determined.

 

Minocycline   Recently, a report aired on CNN and many other news programs that minocycline improved stroke outcomes. This was sparked by a study out of  Israel published in Neurology (Lampl, et.al. 2007) showing a reduction in neurologic deficits in humans following CVA injury as determined by the NIH Stroke Scale, the modified Rankin Scale and the Barthel Index when minocycline was administered within the early 6-24 hour cerebral infarct period. This was an open label, evaluator-blinded study of 152 patients. Additional data supporting this minocycline effect, which is characterized by a suppression of microglia activation and subsequent inflammatory reaction, comes from a study in the department of neurological surgery at University of California at San Francisco (Liu, et.al., 2007) that demonstrated that minocycline administered for 6 weeks post experimentally-induced middle cerebral artery ischemia in rats did not reduce infarct size, but did increase the number of newborn neurons. In addition, results showed improved motor coordination, decreased footfalls in the affected limb and decreased the preferential use of the unaffected limb during motor tasks, and increased learning and memory in spatial tasks,  

 Reading this, I’m sure you can appreciate the potential of minocycline in Alzheimer’s as well. The mechanisms involved appear to be the inhibition of inflammatory activation of microglia and the upregulation of pro-inflammatory cytokines by minocycline resulting in a restoration of neurogenesis or the birth of new neurons. This comes from the studies of Chechniva, et.al. 2006; Ekdahl, et.al. 2003; and Fan, et.al. 2005. Remember my Big 4? 

  This anti-inflammatory effect of minocycline is also found in its matrix metalloproteinase inhibition as well as the above cytokine inhibition (Ahuja, Am J Kidney Dis. 2003 Aug;42(2):376-80). Matrix metalloproteinases can produce injury and lysis of the kidney’s capillary glomerular basement membrane, which is made up of type IV collagen, laminin, fibronectin, and proteoglycans. These destructive enzymes are likely an important participant in the pathogenesis of crescentic glomerulonephritis of the kidney. The Ahuja Galvestion study affirms that tetracycline derivatives such as minocycline inhibit not only the activity of matrix metalloproteinases, but also their production, and have also been investigated for the treatment of disorders in which the metalloproteinase system becomes amplified, such as degenerative osteoarthritis, periodontitis, cancer, and abdominal aortic aneurysm.  The previously mentioned Fan, et.al. in vitro study went on to postulate that because minocycline inhibited the white matter damage by a lipopolysaccharide endotoxin by suppression of the microglial activation, it might be an effective therapeutic treatment for sepsis-induced neuron damage. 

 As you can see, my Alzheimer’s protocol finds its basis in well-controlled studies in reputable scientific journals. Now we have another addition to our Alzheimer’s protocol and I would certainly recommend minocycline as a neuroprotective and preventive. 

 

Namenda (Memantine), works differently from all the above chemicals by specifically blocking the receptors for potentially toxic excitatory neurotransmitters, glutamate and aspartate in the brain. These receptors are called NMDA receptors. These neurotransmitters have been implicated in the development of Alzheimer’s disease by numerous studies. I’ll give you more on this later. Memantine has been used in Germany for treating dementia for over 10 years (Jain, Expert Opin Investig Drugs 2000 Jun;9(6):1397-406). This drug has been found effective in all types of dementia including vascular dementia which is caused by “micro-strokes” or infarcts (Ogrogozo,Stroke 2002 Jul;33(7):1834-9; Mobius and Stoffler, Cerebrovasc Dis 2002;13 Suppl 2:61-6; Gorgula, et.al, Acta Neurochir (Wien) 2000;142(11):1287-92; Pringle et.al, Eur J Neurosci 2000 Nov;12(11):3833-42). These effects of memantine are the reasons that I have included it as part of my “stroke protocol”. Before Namenda was approved for use in the United States by the FDA (after decades of successful use throughout Europe), I used a close cousin (by dimethylation) of this drug called Symmetrel  (Amantadine) which also blocks the NMDA receptor. 

 

Melatonin.    Now, I’m sure that you won’t be surprised by my saying that melatonin has also been shown to inhibit the effects of these excitotoxic NMDA neurotransmitters, and specifically in pyramidal neurons from an area of the brain called the hippocampus which is an area of primary importance in learning and memory (Scaper, et.al. FASEB J 1998 Jun;12(9):725-31).  It is very likely that melatonin is exhibiting some of its anti-Alzheimer’s effects via this mechanism. We’ll discuss this mechanism of action later when we talk about the benefits of melatonin after strokes during which massive amounts of glutamate and aspartate are released and can cause enormous secondary damage to neurons adjacent to the neurons killed off by the stroke itself..

 One of the most devoted scientists researching neurotransmitters and Alzheimer’s is Russel J. Reiter, Ph.D., the author of many scientific papers in reputable scientific  journals as well as a layperson’s book on Melatonin.  He’s been studying the neurotransmitter, melatonin, for the past 40 years, beginning with his association with NASA in the 1960’s. At that time the challenge was to somehow get the astronauts to sleep despite a day-night cycle of 45 minutes during their orbit around the earth. Now as a doctor of neuropharmacology and professor at University of Texas Health Sciences Center at San Antonio, he continues to study the mechanism by which melatonin could prevent the onset of Alzheimer’s. 

 The brains of Alzheimer’s patients are characterized by the insidious development of a proteinaceous substance called beta amyloid. This substance slowly fills in the areas between neurons and glial cells and contributes to the neurofibrillary tangles which probably account for the misguided neurotransmission typical of the Alzheimer’s patient. According to Dr. Reiter, this beta amyoid is composed of oxidized proteins, or protein carbonyls. He has demonstrated that melatonin will prevent the oxidation of these proteins into their beta amyloid form thereby preventing the formation of beta amyloid.  It is only a small jump of logic to understand that young people who secrete large amounts of melatonin from their pineal gland in their brains every night do not get Alzheimer’s disease. It is only after the production of this neurotransmitter slows with age that grandma begins to have difficulty sleeping….and with this begins the slow (or sometimes rapid) decline in cognitive function. 

 Dr Reiter also presents much of the science behind melatonin’s role in augmenting the function of the immune system in its cancer and infection defenses, and, of course, it’s importance in regulating sleep and mood, and its beneficial effects in prevention of cardiovascular disease which is both an inflammatory and an oxidation process. He also points out the effects of melatonin in the prevention of many of the side effects of chemotherapy in cancer treatment. Both his research and his “laybook” are must reads for the layperson, the scientist and the clinician.

 There is also an excellent review published in Biological Signals and Receptors (1998 Jul-Aug: 7(4); 195-219). In this review Bubenik, et.al. document the science behind melatonin’s immuno-hematopoietic (immune system and blood making) benefits, protection against gram negative sepsis (deadly infection)  and shock, prevention of the suppression of the immune system by physiologic or emotional stress and restored immune function after hemorrhagic shock. They demonstrate that melatonin has been proven to regulate the tone of cerebral arteries by receptors in the vascular beds. It may also be through these receptors that melatonin regulates the blood flow to the testicles and ovaries and can function as a female contraceptive. And, of course, not the least of its effects is melatonin’s powerful antioxidant capability as a free radical scavenger as described above. In addition, these authors discuss the scientific studies in which melatonin reduces the incidence and severity of gastric ulcers and prevented severe symptoms of colitis by reducing mucosal lesions and diarrhea.

 Dr. Cardinali, et.al. in a 2002 review of their own studies (Neuroendocrinology Letters 2002 Apr;23 Suppl 1:20-23) show how melatonin decreases the ‘sundowning’ or early evening confusion so often seen in the Alzheimer’s patients. Their study used 9 milligrams every night for 3 years. They also report that it restored sleep patterns and ‘slowed evolution of cognitive impairment’ in these patients. This data is supported by countless well-designed studies published in reputable science journals (Jean-Louis, et.al. Pineal Res 1998 Oct;25(3):177-83, Cohen-Mansfield, et.al. Arch Gerontol Geriatr 2000 Aug 1;31(1):65-76,  Brusco, et.al. Neuroendocrinol Lett 2000;21(1):39-42),  Olde Rikkert and Rigaud Z Gerontol Geriatr 2001 Dec;34(6):491-7).  So is this “alternative medicine” or is it SCIENCE?  At my local hospital, melatonin was banned from use on its campus by the Pharmacy and Therapeutics Committee, which is made up of MD’s.  I was told by these doctors that there was only “anecdotal” data supporting the use of these supplements. I asked them if they had read any of the 300 abstracts I had submitted and they admitted that they had not read a single one. I want you to look at the extensive basic science and clinical studies listed here, then decide. Of course, these MD’s are only clinical doctors and have no PhD in any basic science field and are not trained in research. In addition, they would probably lose their appointment to the committee if they did not attempt to curtail the hospital’s pharmacy budget. I can think of no other reason why they would ban the use of one of the body’s neurotransmitters. Let’s look at more data. 

 As I’ve already pointed out, the antioxidant function of melatonin is one its primary mechanisms of neuroprotection. In addition to melatonin’s receptor-binding of the neurotoxic neurotransmitter function discussed above, some melatonin is normally secreted directly into the cerebrospinal fluid via the choroid plexus in the brain. Maurizi (Med Hypotheses 2001 Aug;57(2):156-60) demonstrates that melatonin passes easily through cell membranes and is concentrated in the mitochondria of the cell. This is the part of the cell that generates the cellular energy required for the cell to perform its function. And because this is the site of energy production, it is also the location of the highest concentration of free radicals, the bad byproducts of combustion, like the exhaust from your car. In Alzheimer’s patients, higher concentrations of these hydroxyl free radicals are produced by the mitochondrial complex IV resulting in mitochondrial damage and subsequently, cell damage or death and neuropathologic changes. Melatonin’s antioxidant function in the mitochondria protects the cell, and low levels of melatonin in Alzheimer’s patients’ mitochondria probably contributes to the disease process. This is quite in line with Dr. Reiter’s research results that we discussed before.

 So is it alternative medicine to be scorned by doctors or is it real science? It is indeed real science, an endogenous or a built-in protective neurohormone, and it deserves real consideration by physicians and laypersons alike as a therapeutic intervention in Alzheimer’s Disease. Does anyone in your family have Alzheimer’s Disease? If so, since there are currently no drugs that give any protection, and given the current state of our knowledge as delineated above regarding the causes of Alzheimer’s and the mechanism by which melatonin prevents or corrects these causes, melatonin would be my first line supplement starting in my mid 40’s to mid 50’s. Take 3 to 9 milligrams per night. Most people sleep like rocks and there should be no ‘hangover’ effect because, as Dr. Reiter has shown, when light strikes the retina in the morning, melatonin’s effect dissipates almost instantly. It sounds like a perfectly designed sleep drug to me. (Could there indeed be an Intelligent Designer?) 

 As I’m writing this, I’ve got to digress for a paragraph and tell you a story. I was sitting in a Continuing Medical Education seminar where the speaker was presenting options for sleep medications. He stated that “there is no study that demonstrates that melatonin is effective as a sleep aide.” (First of all, that is incorrect and for a few well-designed scientific studies see Dr. Reiter’s publications and Jean-Louis, et.al. (Pineal Res 1998 Oct;25(3):177-83), and Brusco, et.al. (Neuroendocrinol Lett 2000;21(1):39-42), and Bubenik, et.al. (Biol Signals Recept 1998 Jul-Aug;7(4):195-219).) Then he said that the new drug Rozarem, a melatonin receptor binding drug has been FDA approved and shown to be an effective sleep aide. No one in the 2000 doctor audience even questioned how, if the drug binds to melatonin receptors in the brain and is an effective FDA approved sleep aide, melatonin itself is not. CME courses are supposed to be scientific and without any commercial bias. How are doctors supposed to think scientifically with this unabashed promotion poorly disguised as CME.  Now don’t misunderstand, Rozarem is a fine medication to induce sleep, but to misrepresent the science as this lecturer did is unacceptable and for the attendees to not pick up on it is lamentable.

 Melatonin is only one component of my Alzheimer’s protocol. I recommend combining this with CoEnzyme Q 10, Acetyl-L-Carnitine, Alpha Lipoic Acid, and DHEA. Please read these sections of this website to appreciate how each of these endogenous chemicals, made in your body, both protect the cells and increase every cell’s energy production thereby allowing the cell to do its job better. If the cell is a heart muscle cell, it will beat stronger. If  it is a skin cell, it will heal cuts and bruises better. If it is a sperm cell, it will increase its motility. AND if it is a brain or nerve cell, it will produce and conduct electricity more efficiently. So you get the idea. When this protocol is given to Alzheimer’s patients, there is an improvement in memory and other cognitive functions. (By the way, these chemicals, produced in our bodies, AND without which we would be DEAD, were also BANNED from that hospital campus along with Melatonin.)  So let’s look at more data. 

 

 Acetyl-L-Carnitine is manufactured in the liver, kidney, and brain by the enzyme ALC-transferase and is best known for its role in long chain fatty acid metabolism and for its role in removing toxic acyl groups from cells thereby improving cellular metabolism. In biochemistry we call this the “carnitine shuttle” because it ‘carries’ the fatty acids across the cell membrane to be used as fuel for the cell’s metabolism. This is important because, while the cell prefers to use oxygen and glucose carried by the blood to the cell for fuel, in conditions of decreased blood flow such as in strokes or the clogged arteries of atherosclerosis or kidney failure, the cell can shift gears and burn fatty acids. This allows the cell to remain viable and continue to do its job. If that cell is a muscle cell in the body or in the heart, it can continue to contract or beat. In fact, the primary fuel for cardiac muscle is fatty acid. If the cell is a neuron in the brain, it can continue to produce the electrical signals and neurochemicals essential for neurotransmission. For you physicians and biochemists, acetyl-L-carnitine facilitates the uptake of acetyl CoA into the mitochondria during fatty acid oxidation, enhances acetylcholine production, and stimulates protein and membrane phospholipid synthesis. Acetyl-L-carnitine, similar in structure to acetylcholine, also exerts a cholinomimetic effect.

 There is a plethora of studies demonstrating L-carnitine improving exercise capability and cardiac function in patients with “claudication” pain in the legs from clogged arteries or decreasing angina pain from clogged arteries in the heart. The size of the damaged area of cardiac muscle after a myocardial infarction or even after heart bypass surgery is also reduced with L-carnitine supplementation and it has an antiarrythmic effect as well. Fatty acids are, I repeat, the major source of oxidative fuel for the heart. As you can see there are hundreds of studies, well designed, both in the basic science literature and the cardiology and thoracic surgery journals. (Lango et.al., Cardiovasc Res 2001 Jul;51(1):21-9; Felix, et.al., Diabetes Res Clin Pract 2001 Jul;53(1):17-24; Akar et.al, Eur J Cardiothorac Surg 2001 Apr;19(4):500-6; Nemoto et.al, Ann Thorac Surg 2001 Jan;71(1):254-9; Lester et.al.,  Mol Cell Biochem 1999 Oct;200(1-2):93-102; Broderick et.al. Mol Cell Biochem 2000 Mar;206(1-2):151-7; Katircioglu, et.al, J Cardiovasc Surg (Torino) 2000 Feb;41(1):45-50; Colonna and Iliceto, Am Heart J 2000 Feb;139(2 Pt 3):S124-30; Krahenbuhl, Schweiz Rundsch Med Prax 1998 Jan 21;87(4):102-7; Jackson, Int J Clin Pract 2001 May;55(4):256-61; Corsi et.al. Angiology 1995 Aug;46(8):705-13; Bartels et.al. Am J Cardiol 1994 Jul 15;74(2):125-30; Terranova and Luca,  Minerva Med 2001 Feb;92(1):61-6; Singh and Aslam,  J Assoc Physicians India 1998 Sep;46(9):801-5; Calvani et.al. Basic Res Cardiol 2000 Apr;95(2):75-83.  I have 75 more papers with similar results. Doesn’t look like “anecdotal” or “alternative” medicine to me. In fact, it’s very interesting reading for any clinically inclined neurobiologist such as I. Let’s look at more. This is fun.

 There are at least as many studies demonstrating the improvement of muscle contraction force and exercise tolerance and neurologic function and insulin resistance and high triglycerides and muscle cramps and hypotension and anemia and respiratory function in end stage kidney disease in patients on dialysis. (Gunal et.al. J Nephrol 1999 Jan-Feb;12(1):38-40; Elisaf et.al. Am J Nephrol 1998;18(5):416-21; Goral, J Ren Nutr 1998 Jul;8(3):118-21; Brass et.al. Am J Kidney Dis 2001 May;37(5):1018-1028; Sakurauchi et.al.  Am J Kidney Dis 1998 Aug;32(2):258-64; Thompson et.al. Clin Nephrol 1997 Jun;47(6):372-8; Hurot et.al. J Am Soc Nephrol 2002 Mar;13(3):708-14.)

 Before erythropoietin therapy for the anemia of hemodialysis, L-carnitine was used and still works for even those patients who become resistant to erythropoietin (Macdougal, Curr Opin Hematol 1999 May;6(3):121-6; Matsumoto et.al. Blood Purif 2001;19(1):24-32; Kletzmayr et.al. Kidney Int Suppl 1999 Mar;69:S93-106; Horl, Nephrol Dial Transplant 2002;17 Suppl 5:56-9). It can even slow the further deterioration of the kidney function (Mister, et.al.  Kidney Int 2002 Mar;61(3):1064-78) and reverse the mental confusion and cognitive decline in chronic hemodialysis patients (DaVanzo and Ullian Clin Nephrol 2002 May;57(5):402-5).

 That should give you some idea of how critical the body’s stores of L-carnitine  are to basic metabolism in every body tissue. By the way, remember that this supplement was BANNED in my local hospital!!!! I hope you appreciate how absurd that is. It should be a mainstay of cardiology and every cardiac bypass patient should be loaded with L-carnitine prior to surgery, and every hemodialysis patient should receive daily doses. I’ll go into more detail on L-carnitine’s innumerable benefits in congestive heart failure and ischemic events such as strokes and heart attacks in other sections. But since we’re interested in Alzheimer’s Disease in this section, we’ll concentrate on that. 

  Here’s another interesting story. I was returning to Houston on a plane when an article in one of the inflight magazines caught my eye. It was a human interest story about Dr. Bruce Ames, one of the top 400 cited scientists in the world and a biochemist at Berkeley. The story was about his interest in acetyl-l-carnitine and Alzheimer’s Disease, an interest that was sparked by his recent trip to Italy where it seemed to him that everyone was taking it for a ‘pick-me-up’. The next day I called him and told him about my work in the neurochemistry of this compound and how it played a critical role in my stroke protocol. He seemed quite interested and he was very accommodating.  He emailed me some of his studies. I’ll try to summarize some of these results here.

 True to his reputation, he elegantly combined behavior, electrophysiology and neuropharmacology in several well-designed studies. 

I’m going to paraphrase the results of these studies and I’m sure if I get them wrong, Dr. Ames will correct me. In the behavioral studies, he placed young and old rats in a small tank of water with an island in the center. The young rats had no difficulty finding the island and crawling up onto the “dry land” thereby avoiding certain drowning. The old rats, on the other hand, would swim around aimlessly and if they were not rescued by the experimenter, would have drowned. After loading the older rats with acetyl-l-carnitine, they performed the task like the young rats, finding the island easily thereby saving themselves. 

 In the electrophysiologic studies, Dr. Ames recorded with microelectrodes, the firing of neurons in the brains of old rats. He noticed that when compared to the young rat group, he could identify many more active neuronal firings in the young rats than in the older ones. However, when he loaded the older rats with acetyl-l-carnitine, many more neurons “came to life” and began to fire away vigorously. This was indeed an exciting finding. Apparently, the acetyl-l-carnitine provided the quiescent neurons with access to free fatty acid energy stores via the carnitine shuttle as I discussed previously. 

 Dr. Ames was concerned, however, that if he increased the metabolic rates of these neurons, there would be a resulting increase in the free radical production, the byproducts of energy production of cells. These free radicals would damage these old neurons and they would then die off. The animal would then be back in the same or worse state than it had been prior to the administration of the acetyl-l-carnitine. So Dr. Ames measured the amount of free radicals in the intercellular fluid after acetyl-l-carnitine dosing and indeed the levels were unacceptably elevated. He then administered alpha lipoic acid to these animals and found that he could reduce these free radical levels back to normal, thereby protecting the neurons that he had fired up with the acetyl-l-carnitine.  Dr. Ames used alpha lipoic acid because it is the chemical produced in the mitochondria of all cells to perform exactly this function of binding up the free radicals produced by energy metabolism of the cells thereby protecting them from their own “exhaust”. Fascinating application of basic neuro/biochemistry isn’t it?

 This biochemistry can be applied to all senescent or old cells, essentially restoring their function. In the case of Alzheimer’s disease, this simple application of neurochemistry would restore the function of at least some neurons in the brains of these patients. Since levels of both acetyl-l-carnitine and alpha lipoic acid are low in both old rats and old people, and since these substances are endogenous (normally present) chemicals in normal brains and not “drugs”, there is no potential downside to restoring these levels to normal in these senescent brains.

 Alpha lipoic acid. Now let’s talk about ALA.  For this discussion I’m not citing references because the best reference is your local biochemistry book. As I mentioned in the above section, ALA performs a very important function in all cells. We’ll get back to the antioxidant function of ALA several paragraphs from here, but first let’s discuss the larger role of ALA that most doctors have long since eliminated from their brains. It is most importantly involved in the basic process of turning food into energy. I’ll show you how. 

 Food, sugar and fats, are oxidized by the body by combining them with oxygen from the lungs. In the mitochondria of every cell, these precursor products then undergo a decarboxylation, that is, a splitting off of a small acid side chain from these molecules. It is an enzyme complex of ALA that does this work. The acid released in this reaction is converted to carbon dioxide and “blown off” by the lungs. This complicated process is called “oxidative decarboxylation of alpha-keto acids”. The partially processed food molecules are then able to enter the Kreb’s cycle to be converted into energy (pyruvate into acetyl-coenzyme A). So, in effect, ALA is critical in the conversion of blood sugar into energy for muscle contraction, nerve conduction, cell replication, and for every bodily process.  

 ALA is made inside the cell from the dietary amino acid cysteine, but it is also taken into the cell from outside as would occur with supplementation. Once inside the cell it is converted to a substance called dihydrolipoic acid and thereby becomes one of the most powerful “reducing” agents in the body. That means that it binds up free radicals and is a powerful antioxidant. Isn’t it interesting that ALA is present and produced  inside the mitochondria where oxidative phosphorylation occurs and where the free radical  “exhaust” from the energy production needs to be cleaned up quickly before it damages the cellular DNA…or the rest of the body? Indeed, it is a fascinating design.

 So we have identified two functions of ALA without which we could not survive, energy production and free radical scavenging. It’s powerful free radical reducing potential actually also makes it a “chelating” agent for heavy metals such as iron, cadmium, and mercury, and copper (Yamamoto et.al Free Radic Res 2001 Jan;34(1):69-80) and is actually used in Europe for heavy metal toxicity syndromes. 

 On one end of the ALA molecule, there is a carboxylic acid and therefore it is quite water soluble or hydrophilic. It can therefore enter any body tissue compartment that is primarily water. The rest of the molecule has 8 carbon atoms and this renders it very lipophilic or fat soluble and allowing it to enter any body compartment that is primarily fat. ALA can, as a result of its molecular structure, freely function as an antioxidant in any part of the body making it a universal antioxidant.

 It can also rejuvenate the antioxidant capability of vitamin E, a fat soluble dietary antioxidant, and vitamin C, a water soluble antioxidant. This is called “redox cycling”. The ALA molecule can donate an electron or hydrogen atom to these vitamins after they have had an electron removed by a free radical thereby restoring the vitamin’s ability to donate that electron or hydrogen atom to another free radical rendering it harmless to the body. I’ll repeat this another way. After vitamin E reduces a free radical, it is oxidized. ALA in turn reduces the oxidized vitamin E restoring its ability to reduce another free radical. 

 This cooperation and interaction of the antioxidants is readily seen in a study by Schneider and Elstmer (Antioxid Redox Signal 2000 Summer;2(2):327-33) in which the diene conjugation of LDL cholesterol was investigated. The initial reduction was performed by co-Enzyme Q10. After 80% of the Q10 is oxidized, vitamin E began its reduction. This study demonstrates what may be the physiologic sequence of events by the body to prevent the oxidation of cholesterol. Finally, the LDL-bound Q10 was rapidly reduced by ALA, and this reduction occurred 10 times faster than by vitamin C. Why would we not have all our heart disease patients on a protocol of CoQ10, ALA, and antioxidants? 

 Recently, a study received a big splash of publicity on all television news channels and internet pages that showed that taking too much vitamin E resulted in conditions where vitamin E becomes a “prooxidant”. That means that under those conditions, vitamin E can itself function as a free radical. Many people quit taking vitamin E as a result. All antioxidants have potential to become prooxidants under certain conditions. However, in the presence of ALA, this should not occur, a biochemical principle overlooked in all the publicity storm.  ALA, therefore, is probably essential in maintaining the antioxidant function of vitamins E and C in the human body.

 Now that we’ve covered that, you can see why Dr. Ames used ALA to reduce the free radicals in his studies mentioned above in the discussion of acetyl-L-carnitine. Zang, et.al. (Neurosci Lett 2001 Oct 26;312(3):125-8) have shown that ALA protects cortical neurons against cell death by beta-amyloid by a process of antioxidation similar to that of melatonin discussed above. Hager, et.al. (Arch Gerontol Geriatr 2001 Jun;32(3):275-282) also demonstrated a halting of cognitive decline in Alzheimer patients receiving ALA.  Remember the acetylcholine hypothesis of Alzheimer’s that I mentioned at the beginning of this section? With regard to this, Drs. Haugaard and Levin (Mol Cell Biochem 2000 Oct;213(1-2):61-3) found that the reduced form of ALA increased the activity of choline acetyltransferase, the rate limiting enzyme for the production of acetylcholine.

For more information on ALA in the prevention of complications of diabetes such as neuropathy and kidney disease, see that section on the main menu.

Coenzyme Q10:   Now let’s talk about Q10.  

This section is still under construction. Stand by for the “rest of the story”.