Galantamine Can Modify Alzheimer's Disease

Galantamine Can Help You Get Your Bearings

Galantamine Can Modify
Alzheimer's Disease

In which, among other things, a mouse called Linus
demonstrates a certain aptitude for navigation
By Will Block

hen Linus Pauling went for a walk one evening at his ranch on the magnificently rugged Big Sur coast of California, he slipped, fell off a cliff, and landed, miraculously, on a narrow ledge far above the jagged rocks and roiling surf. Unable to climb back up or to summon help (cell phones did not yet exist), and knowing that there was no chance of a rescue until daybreak, he realized that he would have to keep himself awake all night so as to avoid falling off the ledge in his sleep.

He needed a mental challenge, and he soon found one. Contemplating the stars on that beautifully clear night, he decided to work out the mathematical theory of celestial navigation, about which he knew nothing. Being well versed in mathematics and physics (he had long ago written superb textbooks of atomic physics and quantum mechanics, among others), he set about deriving the necessary equations in his head, from scratch. In that one long, perilous night, he accomplished this formidable task. For a man who was a giant among geniuses, perhaps it was as easy as falling off a ledge.

Thankfully, Pauling was indeed rescued the next morning—cold, tired, and hungry but none the worse for wear, and knowing a lot more about one aspect of science than he had known the day before.

Lab Mice May Be Smarter Than We Think

Of course, sailors worldwide had long been using the principles of celestial navigation, without necessarily understanding the mathematics involved and with varying degrees of success (those who were not good at it tended to vanish without a trace). With only the ever-changing positions of the sun and moon and stars to guide them across the vastness of the sea, they depended for their very lives on their intimate knowledge of the heavens. Somehow they had to interpret what they saw in terms of the location of their landfall, which was out there … somewhere.

Well, that's all well and good, but what does any of this have to do with life enhancement (apart from the rather obvious need, for starters, to stay alive)? Patience, please. We now turn our attention to laboratory mice, which, although not exactly scientific geniuses, are often required to be navigators of a sort. Using visual cues not unlike the stars in the sky, they must guide themselves to a kind of landfall of their own. The setup is called the Morris water maze, and its a favorite tool used by researchers to study the ability of rodents to learn and remember useful visual information, especially if they're cognitively impaired by a disorder such as Alzheimer's disease.

How Linus Uses His Smarts to Triumph in a Perilous Situation

Aha! Now we're talking, right? Were going to find out what effect the nutritional supplement galantamine, a plant-derived alkaloid, had on the memory of Alzheimer's-prone mice being tested in a Morris water maze. Some readers may remember a recent article ( CDP-Choline Helps with Memory, March 2005) that described what it must be like to be in the water maze, swimming for one's life. In a nutshell, heres how it works:

The maze is actually just a circular tank with smooth walls that offer no chance of escape. Often the entire tank is painted black, so the water looks black and is therefore opaque. Hidden just below the surface, somewhere in the tank, is a small platform that the mouse (lets call him Linus) can climb up on, if he should stumble upon it while desperately seeking a way out of his predicament. And if he does find it (whew!), he's going to have to find it again if the Big Bad Researcher puts him in the tank again later on—which the BBR will most certainly do, over and over and over.

But will Linus have any better chance of finding the platform the next time? Yes, because the tank is not entirely featureless: located around its periphery are several fixed objects or painted-on shapes, such as a square, a circle, a triangle, etc. These visual cues are the only distinctive things Linus can see in his surroundings. They are, for all practical purposes, the stars in his nighttime sky. With repeated trials in the tank (starting from a different place each time, to make it more challenging), Linus will soon begin to associate the location of his landfall—that blessed platform—with its position relative to the stars. He will become, in effect, a furry little celestial navigator. (Give that mouse a tiny Nobel Prize or two!)

But What About Mice with Alzheimer's?


In one way or another, we look to the heavens to navigate our way through life. To find our destination, we need to get our bearings. This article explains.
Now, two questions arise: how quickly will Linus learn this life-saving skill, and how well will he remember it after a significant time has elapsed (a few days, say, which is equivalent to a few months in human terms)? If Linus is true to his namesake, he'll be brilliant—but now it's time to get real and talk about ordinary mice. We can test them on the two questions just asked, but we also want to test mice that are prone to Alzheimer's disease, because that's where the questions acquire special significance.

Researchers can't just sit around waiting for some of their mice to develop Alzheimer's, so they've devised a means for genetically engineering mice to be exceptionally prone to age-related cognitive impairment and dementia. Insofar as one can discern these things in a mouse, the condition strongly resembles Alzheimer's, and such transgenic mice are therefore regarded as suitable subjects for research on this disease.

Senile Plaque Destroys Cognitive Functions

A team of researchers in Belgium recently conducted experiments with galantamine and another anti-Alzheimer's agent, the prescription drug memantine, using a transgenic mouse strain called APP23.1* In these mice, an inserted human gene responsible for synthesizing a protein called human amyloid precursor protein (hAPP) is expressed 7 times more strongly than is the mouse's gene for synthesizing its own version of APP. This protein is the precursor to amyloid-beta, a family of smaller, highly neurotoxic proteins that form the bulk of the destructive brain deposits called senile plaques.


*Although it has long been used as a nutritional supplement, galantamine is also sold (at considerably greater cost) as a prescription drug called Razadyne™ (which was until recently called Reminyl®).


Not to be confused with the atherosclerotic plaques that clog our arteries, senile plaques form in the brain itself and are one of the main neuropathological hallmarks of Alzheimer's disease. (For some astonishing recent results pertaining to another hallmark, neurofibrillary tangles, see the sidebar.) Amyloid-beta is believed to be the result, at least in part, of oxidative brain damage caused by free radicals, and it compounds the problem by contributing to the production of "more" free radicals. Thus it is both a cause and an effect of the brain damage associated with this terrible disease.

Stunning News Regarding Alzheimer's Disease

"I was astonished. I didn't believe the results when I saw them. When I saw the memory getting better, I actually thought I had done something wrong in the experiment."1 So said Dr. Karen Ashe, of the University of Minnesota Medical School, recently; she was the leader of a team of researchers from Minnesota, Florida, and Massachusetts who were investigating the role of neurofibrillary tangles (NFTs) in Alzheimer's disease.2

As the name implies, NFTs are tangled-up fibers found inside certain neurons—mainly the neurons of the hippocampus and cerebral cortex. Together with senile plaques (which reside outside the neurons), NFTs have long been associated with the cognitive deficits and brain damage that characterize Alzheimer's disease.

Dr. Karen Ashe
NFTs are composed largely of a mutant form of an otherwise benign protein called tau (rhymes with wow). The tau protein is coded for by the tau gene in our DNA, and a mutation in that gene produces the mutant protein. The American researchers created a strain of mice whose DNA contains the mutant gene, making their brains particularly prone to the formation of NFTs. The gene can be suppressed, however, by a drug called doxycycline, enabling researchers to turn off production of the mutant tau protein at will.

In an elegant series of experiments with these transgenic mice, and using the Morris water maze to test their learning and memory abilities, the researchers discovered something astonishing: suppressing the formation of NFTs at 4 months of age or beyond didn't just stop memory function from further deterioration, as would be expected—it actually improved it, despite the existing brain damage! Furthermore, NFTs continued to accumulate in the mouse brains, indicating that they were no longer dependent on the mutant tau gene, as had been true when the mice were only 2 1/2 months old. And despite the continued accumulation of NFTs after the gene was turned off, the further loss of neurons and brain weight was halted!

This is stunning. It implies—in this transgenic mouse model, at least—that NFTs do not necessarily cause neuronal death, as had long been believed, and that the processes leading to their formation are not necessarily related to those that cause memory loss and other forms of cognitive impairment. And it demonstrates that the NFTs remaining after suppression of the mutant gene are not sufficient to disrupt cognitive function.

The recovery of memory that should have been lost forever in these mice suggests one of two things: (1) their initial memory loss (before the mutant gene was suppressed) was caused by a reversible dysfunction of the neurons rather than by irreversible structural damage to the neurons; or (2) if it was caused by structural damage, the damage was reversible, i.e., the neurons were somehow able to repair themselves after the gene suppression, allowing recovery of function.

Either way, this bodes well for humans, because if it turns out that these results apply to us too (always a big if), they offer the hope that recovery of lost cognitive function may be possible in the early stages of Alzheimer's disease and, perhaps, in other neurodegenerative diseases whose development is related in some way to tau. Wow!

References

  1. Fox M. Mouse study suggests Alzheimer's damage reversible. Reuters Health report, July 14, 2005.
  2. SantaCruz K, Lewis J, Spires T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005 Jul 15;309:476-81.

The brain damage manifests in many ways, including a progressively impaired ability to learn and to remember. In the APP23 mice, which are highly prone to developing these Alzheimer's-like symptoms, the effects usually begin to appear at about 6 weeks of age (young adult). That's when the Belgian researchers began their experiments, which were designed to see whether galantamine or memantine could provide a long-term protective effect against the ravages of the disease.

How to Get a Belgian Mouse Pumped

With the mice under anesthesia, the Belgian researchers slit the skin of their upper backs and implanted tiny pumps set to deliver a minuscule but steady trickle of an aqueous solution for at least 4 weeks at a stretch. The experimental protocol called for 9 mice to have pumps that delivered 1.3 mg of galantamine per kg of body weight daily; another 9 had pumps that delivered twice as much: 2.6 mg. (These dosages, called low dose and high dose, respectively, were chosen so as to have clinical relevance compared to the dosage range typically used for humans.) Another 17 mice (9 + 8) similarly received low-dose or high-dose memantine, and 9 control mice received saline solution.

After 4 weeks, the pumps were removed and replaced with new ones, and 4 weeks after that, those pumps were removed. The researchers then allowed a 3-week washout period for the symptomatic effects caused by the treatments to dissipate. Now the mice were 17 weeks old (late middle age), and the real work began. All five groups were put through the rigors of the Morris water maze, 4 times daily for 8 days. They all learned to find the hidden platform, and day by day, all of them showed fairly steady improvement (shorter total distances swum and less time taken).

Galantamine Improved Visual-Spatial Memory

Did the galantamine or memantine mice do better than the controls? No, they did not—how disappointing! But wait, this experiment was not over. The payoff came 4 days after the last trial, when the researchers tested the mice once again. This time, both the galantamine mice and the memantine mice did significantly better than the controls, indicating that they had a better grasp of their previously acquired navigational skill, which depended on visual-spatial learning and memory.


The galantamine mice had a better
grasp of their previously acquired
navigational skill, which depended on
visual-spatial learning and memory.


For galantamine, the low dose proved effective in improving memory, but the high dose did not. This finding jibed with the results of clinical trials of galantamine in humans, in which the efficacy has been found to increase with increasing dosages, up to about 24 mg/day, after which it begins to fall off.2 The researchers reanalyzed the mouse data with the inclusion of data that had been obtained previously using normal (nongenetically modified, hence non-Alzheimers-prone) mice in the exact same water-maze procedure. The results remained the same: the low dose of galantamine was effective in improving visual-spatial memory, whereas the high dose was not.

Galantamine Modifies the Course of Alzheimer's

The researchers believe that the significance of their study lies in the demonstration that galantamine (and memantine) do not just ameliorate the symptoms of Alzheimer's disease, but also modify the course of the disease itself. They stated,

By and large, our data clearly demonstrate disease-modifying efficacy of galantamine and memantine on the cognitive impairment in the APP23 model. … Although disease-modifying efficacy is obvious, the present data set does not allow statements regarding true neuroprotective effects in APP23 brain.

The invaluable property of neuroprotection has, however, been ascribed to galantamine in studies by other researchers, and some of these studies have been discussed previously in Life Enhancement (see, e.g., Galantamine Suppresses Brain-Cell Suicide and Galantamine Helps Protect Your Neurons in the February 2004 and April 2005 issues, respectively).

Somewhere, Over the Horizon …

In our sophisticated, high-tech world, it's remarkable and gratifying that something as simple as the Morris water maze can help us shed new light on one of the most vexing problems in modern healthcare: how best to treat Alzheimer's disease. Thanks to the lowly but clever mouse (the rat too), we can conduct various tests far more quickly and efficiently than would be possible with humans. As they swim for science, they enable us, little by little, to improve our navigation of the vast sea of ignorance lying between us and the knowledge that exists somewhere over the horizon.

References

  1. Van Dam D, De Deyn PP. Cognitive evaluation of disease-modifying efficacy of galantamine and memantine in the APP23 model. Eur Neuropsychopharmacol 2005 [online preprint].
  2. Loy C, Schneider L. Galantamine for Alzheimer's disease (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. John Wiley & Sons, Chichester, UK.

Dual-Action Galantamine

Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.

For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.

It’s also a good idea to take the following:

  • Green tea polyphenols, a class of antioxidants, operating together as a system, that can also fight amyloid-beta toxicity
  • Vitamin C and Vitamin E, which have been shown to work together to help protect your brain's hotbeds of free radical activity
  • Turmeric curcuminoids, a system of antioxidants that helps protect your neurons from damage or death caused by amyloid-beta
  • Folic acid, vitamin B6, and vitamin B12, important vitamins that help prevent damage to mitochondria (where they help repair DNA damage), cofactor the production of nitric oxide, and reduce levels of homocysteine (a neurotoxin)
  • Lithium, an important brain food that is found in the bottled waters of American and European health spas ... that also lowers the toxicity of amyloid-beta while causing an increase in neurotrophic factors that help induce neurons to repair themselves when under stress ... that helps cause an increase in gray matter and helps enhance neurogenesis of hippocampal neurons


Will Block is the publisher and editorial director of Life Enhancement magazine.

Ingredients in this Article

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