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.
“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 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, 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.
Passing along the message
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.
-Source: sciencedaily.com
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