From: 23x11.5c@gmail.com   
      
   Blocking Brain’s ‘Internal Marijuana’ May Trigger Early Alzheimer’s   
   Deficits   
      
       
   Neuroscience News     
   June 18, 2014     
   Electrophysiology, Featured, Neurology   
      
   A-beta, a substance suspected as a prime culprit in Alzheimer’s disease, may   
   start impairing learning and memory long before plaques form in the brain.   
      
   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, 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.   
      
   â€œThe hippocampus tells us where we are in space at any given time,â€� 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.â€�   
      
   This image shows the location of the hippocampus in the brain.   
   Researchers analyzed A-beta’s effects on the hippocampus. Credit Gray’s   
   Anatomy.   
   Surprise finding   
      
   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 pyramidal cells. 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,    
   hysiologically 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   
   â€œcatâ€� — 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 blanketâ€� 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.   
      
   Passing along the message   
      
   But when the news is particularly significant, pyramidal cells squirt out   
   their own “no, this is important, you shut up!â€� 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 nerve   
   cells, 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.   
      
      
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    * Origin: you cannot sedate... all the things you hate (1:229/2)