Going to Pot May Lower Alzheimer's Risk

October 19, 2006 Michael Smith Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania ATLANTA, Oct. 19 Those years of pot smoking a generation ago may have created an unexpected legacy for baby boomers a lower risk of Alzheimer's disease. That's the implication of animal research presented by Gary Wenk, Ph.D., of Ohio State University in Columbus at the Society for Neuroscience meeting here. As the boomers hit the age where Alzheimer's begins to show itself, it may be that if "they smoked marijuana in the '60s and '70s they don't get the disease, because of that behavior," said Dr. Wenk. He based the assertion on research he and colleagues have done with rats, not usually known for developing Alzheimer's, nor for that matter, for smoking marijuana. But as the animals age, Dr. Wenk said, they develop inflammation in parts of the brain analogous to the parts damaged by inflammation in people with Alzheimer's. Recent research in other fields suggested that cannabinoids the active ingredients in marijuana can cross the blood-brain barrier, even at low doses, and can reduce inflammation, Dr. Wenk said. So, in young rats, Dr. Wenk and colleagues created brain inflammation by infusing nanogram quantities of lipopolysaccharide and then treated them with a synthetic cannabinoid called WIN-55212-2. "We saw an 80% to 90% drop in the inflammation in the brain," he said, "and also the impairment in memory that inflammation produces could be reversed." But that "wasn't actually a big surprise," Dr. Wenk said. Many anti-inflammatory agents have been shown to have the same effect, but only in young rats. In older animals, the effects are usually muted, perhaps by the loss of the appropriate receptors in the brain. What was both surprising and exciting, he said, was what happened when 24-month-old rats equivalent to about 70 years old in human terms were given the cannabinoid, as doses of either 0.5 or 2.0 mg/kg of body weight. The old rats like old humans had inflammation in some areas of the brain, as shown by activated microglia. Dr. Wenk said. When they were given the cannabinoid, "we saw a 50% to 90% drop in the number of activated microglia, depending on the area you looked at," he said. What's more, he said, the mice improved their performance on a standard memory test the water maze by about 50%. In the test, rats are placed in a tank of water that has a submerged platform on which they can rest. Rats usually take one or two minutes to find the platform the first time, but young rats only take a few seconds to find it again when they are subsequently replaced in the tank. Old rats, on the other hand "typically never really get it," Dr. Wenk said. But when treated with the cannabinoid, their performance would drop from perhaps 300 seconds to 150, he said an improvement, even though they weren't as quick as young rats. The implication of the study is that treatment with an anti-inflammatory agent can restore some cognitive function and may stop the long decline in cognition that is characteristic of Alzheimer's, Dr. Wenk said.

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Press Release Marijuana's Active Ingredient Shown to Inhibit Primary Marker of Alzheimer's Disease Discovery Could Lead to More Effective Treatments LA JOLLA, CA, August 9, 2006 - Scientists at The Scripps Research Institute have found that the active ingredient in marijuana, tetrahydrocannabinol or THC, inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease. In fact, the study said, THC is "a considerably superior inhibitor of [amyloid plaque] aggregation" to several currently approved drugs for treating the disease. The study was published online August 9 in the journal Molecular Pharmaceutics, a publication of the American Chemical Society. According to the new Scripps Research study, which used both computer modeling and biochemical assays, THC inhibits the enzyme acetylcholinesterase (AChE), which acts as a "molecular chaperone" to accelerate the formation of amyloid plaque in the brains of Alzheimer victims. Although experts disagree on whether the presence of beta-amyloid plaques in those areas critical to memory and cognition is a symptom or cause, it remains a significant hallmark of the disease. With its strong inhibitory abilities, the study said, THC "may provide an improved therapeutic for Alzheimer's disease" that would treat "both the symptoms and progression" of the disease. "While we are certainly not advocating the use of illegal drugs, these findings offer convincing evidence that THC possesses remarkable inhibitory qualities, especially when compared to AChE inhibitors currently available to patients," said Kim Janda, Ph.D., who is Ely R. Callaway, Jr. Professor of Chemistry at Scripps Research, a member of The Skaggs Institute for Chemical Biology, and director of the Worm Institute of Research and Medicine. "In a test against propidium, one of the most effective inhibitors reported to date, THC blocked AChE-induced aggregation completely, while the propidium did not. Although our study is far from final, it does show that there is a previously unrecognized molecular mechanism through which THC may directly affect the progression of Alzheimer's disease." As the new study points out, any new treatment that could halt or even slow the progression of Alzheimer's disease would have a major impact on the quality of life for patients, as well as reducing the staggering health care costs associated with the disease. Alzheimer's disease is the leading cause of dementia among the elderly, and the numbers are growing. The Alzheimer's Association estimates 4.5 million Americans have the disease, a figure that could reach as high as 16 million by 2050. A survey by the National Center for Health Statistics noted that half of all nursing home residents have Alzheimer's disease or a related disorder. The costs of caring for Alzheimer's patients are at least $100 billion annually, according to the National Institute on Aging. Over the last two decades, the causes of Alzheimer's disease have been clarified through extensive biochemical and neurobiological studies, leading to an assortment of possible therapeutic strategies including interference with beta amyloid metabolism, the focus of the Scripps Research study.

The cholinergic system - the nerve cell system in the brain that uses acetylcholine (Ach) as a neurotransmitter - is the most dramatic of the neurotransmitter systems affected by Alzheimer's disease. Levels of acetylcholine, which was first identified in 1914, are abnormally low in the brains of Alzheimer's patients. Currently, there are four FDA-approved drugs that treat the symptoms of Alzheimer's disease by inhibiting the active site of acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine. "When we investigated the power of THC to inhibit the aggregation of beta-amyloid," Janda said, "we found that THC was a very effective inhibitor of acetylcholinesterase. In addition to propidium, we also found that THC was considerably more effective than two of the approved drugs for Alzheimer's disease treatment, donepezil (Aricept ) and tacrine (Cognex ), which reduced amyloid aggregation by only 22 percent and 7 percent, respectively, at twice the concentration used in our studies. Our results are conclusive enough to warrant further investigation." Other authors of the study, titled "A Molecular Link Between the Active Component of Marijuana and Alzheimer's Disease Pathology," include Lisa M. Eubanks, Claude J. Rogers, and Tobin J. Dickerson of The Scripps Research Institute, the Skaggs Institute for Chemical Biology, and the Worm Institute for Research and Medicine; and Albert E. Beuscher IV, George F. Koob, and Arthur J. Olson of The Scripps Research Institute. The study was supported by the Skaggs Institute for Chemical Biology at Scripps Research and the National Institutes of Health. About The Scripps Research Institute The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009. For more information contact: Keith McKeown 10550 North Torrey Pines Road La Jolla, California 92037 Tel: 858.784.8134 Fax: 858.784.8118 kmckeown@scripps.edu Copyright 2006 TSRI. All rights reserved. Reproduction in whole or in part in any form or medium without express written permission of TSRI is prohibited.