Brain researchers are convinced that a sticky and mysterious substance called beta-amyloid is a “black hat” in the neurodegenerative process resulting in Alzheimer’s disease. But nobody’s been sure how beta-amyloid, a sawed-off fragment of a larger protein whose natural role in the body is also obscure, goes about its dastardly work.
Because beta-amyloid is the chief constituent of the notorious gummy deposits, called plaques, that overpopulate the brains of Alzheimer’s patients, it made sense to see if finding pharmacological ways to rid patients’ brains of plaque would pay off. Billions of dollars in failed clinical trials later, that utterly reasonable hypothesis looks shaky.
A new study spearheaded by Stanford neurobiologist Carla Shatz, PhD, and published in Science has breathed gale-speed wind into another equally reasonable conjecture: Suppose beta-amyloid molecules are wrecking the brain long before they coalesce into those hallmark plaques? Her team’s findings offer a better understanding of just how this happens.
To quote from our news release accompanying the study’s publication:
Beta-amyloid begins life as a solitary molecule but tends to bunch up — initially into small clusters that are still soluble and can travel freely in the brain, and finally into the plaques that are hallmarks of Alzheimer’s. The study showed for the first time that in this clustered form, beta-amyloid can bind strongly to a receptor on nerve cells, setting in motion an intercellular process that erodes their synapses with other nerve cells.
Synapses are the intricate contact points through which one nerve cell conveys a signal to the next. A healthy adult human brain probably has well over a quadrillion such connections. Synapses define the brain circuitry that underlies our memories, our every thought and emotion, and our voluntary and involuntary muscular exertions.
It was known already that as Alzheimer’s progresses, the destruction of nerve cells is preceded by wholesale synapse destruction. The new study shows how that destructive process probably comes about.
Working with human brain tissue as well as with mice that have been genetically engineered so that their brains are essentially bathing in beta-amyloid throughout their lives, Shatz and her colleagues puzzled out the molecular details of how the binding of beta-amyloid to a particular receptor sitting on nerve-cell surfaces (presumably for a perfectly good reason, which Shatz has explored in earlier research) triggers the activation of cofilin, an enzyme (a protein molecule that acts as a machine) inside nerve cells whose job it is to tear down the nano-skeletons that maintain nerve cells’ – and their synapses’ – structure. Too much cofilin activity, bye-bye synapse.
With a little help from Big Pharma (or a scrappy biotech) these findings could someday lead to the development of some kind of decoy molecule that lures beta-amyloid in its soluble form away from that wrongfully aroused receptor, puts the chill on cofilin, and sparing our synapses – and our memories – from oblivion.
Previously: Black hat in Alzheimer’s, white hat in multiple sclerosis?, Protein known for initiating immune response may set our brains up for neurodegenerative disorders, When brain’s trash collectors fall down on the job, neurodegeneration risk picks up and Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed
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