Blocking brain's 'internal marijuana' may trigger early Alzheimer's deficits, study shows

June 18, 2014, Stanford University Medical Center
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

A new study led by investigators at the Stanford University School of Medicine has implicated the blocking of endocannabinoids—signaling substances that are the brain's internal versions of the psychoactive chemicals in marijuana and hashish—in the early pathology of Alzheimer's disease.

A substance called A-beta—strongly suspected to play a key role in Alzheimer's because it's the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer's—may, in the disease's earliest stages, impair learning and memory by blocking the natural, beneficial action of endocannabinoids in the brain, the study demonstrates. The Stanford group is now trying to figure out the molecular details of how and where this interference occurs. Pinning down those details could pave the path to new drugs to stave off the defects in learning ability and memory that characterize Alzheimer's.

In the study, to be published June 18 in Neuron, researchers analyzed A-beta's effects on a brain structure known as the hippocampus. In all mammals, this midbrain structure serves as a combination GPS system and memory-filing assistant, along with other duties.

"The hippocampus tells us where we are in space at any given time," said Daniel Madison, PhD, associate professor of molecular and cellular physiology and the study's senior author. "It also processes new experiences so that our memories of them can be stored in other parts of the brain. It's the filing secretary, not the filing cabinet."

Applying electrophysiological techniques to brain slices from rats, Madison and his associates examined a key hippocampal circuit, one of whose chief elements is a class of nerve cells called . They wanted to see how the circuit's different elements reacted to small amounts of A-beta, which is produced throughout the body but whose normal physiological functions have until now been ill defined.

A surprise finding by Madison's group suggests that in small, physiologically normal concentrations, A-beta tamps down a signal-boosting process that under certain conditions increases the odds that pyramidal nerve cells will transmit information they've received to other nerve cells down the line.

When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input—such as might accompany falling into a hole, burning one's finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell "cat"—are firmly stored in the brain's memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells—effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of "wet blanket" nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells' transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance—the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

But when the news is particularly significant, pyramidal cells squirt out their own "no, this is important, you shut up!" chemical—endocannabinoids—which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison's research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron's endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to , this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ's sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer's disease.

Exactly how A-beta blocks endocannabinoids' action is not yet known. But, Madison's group demonstrated, A-beta doesn't stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car's ignition switch won't do much good if your battery is dead.)

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta's nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb's active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

"Endocannabinoids in the brain are very transient and act only when important inputs come in," said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. "Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It's like listening to five radio stations at once."

Besides, flooding the brain with external cannabinoids induces tolerance—it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids' ability to do their crucial job of opening the gates of learning and memory.

Explore further: Mapping blank spots in the cheeseboard maze

Related Stories

Mapping blank spots in the cheeseboard maze

March 22, 2013
(Medical Xpress)—During spatial learning, space is represented in the hippocampus through plastic changes in the connections between neurons. Jozsef Csicsvari and his collaborators investigate spatial learning in rats using ...

Investigators discover how key protein enhances memory and learning

May 2, 2014
Case Western Reserve researchers have discovered that a protein previously implicated in disease plays such a positive role in learning and memory that it may someday contribute to cures of cognitive impairments. The findings ...

Compound reverses symptoms of Alzheimer's disease in mice, research shows

May 20, 2014
A molecular compound developed by Saint Louis University scientists restored learning, memory and appropriate behavior in a mouse model of Alzheimer's disease, according to findings in the May issue of the Journal of Alzheimer's ...

Study reveals potential role of 'love hormone' oxytocin in brain function

August 4, 2013
In a loud, crowded restaurant, having the ability to focus on the people and conversation at your own table is critical. Nerve cells in the brain face similar challenges in separating wanted messages from background chatter. ...

Research illuminates molecular mechanism for why stimulating environment may protect against Alzheimer's disease

March 6, 2013
"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer's disease. Previous studies have shown that keeping the mind active, exercising and social interactions may ...

Discovery sheds new light on marijuana's anxiety relief effects

March 6, 2014
An international group led by Vanderbilt University researchers has found cannabinoid receptors, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight ...

Recommended for you

Research shows signalling mechanism in the brain shapes social aggression

October 19, 2018
Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has ...

Good spatial memory? You're likely to be good at identifying smells too

October 19, 2018
People who have better spatial memory are also better at identifying odors, according to a study published this week in Nature Communications. The study builds on a recent theory that the main reason that a sense of smell ...

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Weight loss success linked with active self-control regions of the brain

October 18, 2018
New research suggests that higher-level brain functions have a major role in losing weight. In a study among 24 participants at a weight-loss clinic, those who achieved greatest success in terms of weight loss demonstrated ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.