Key features of Alzheimer's, which affects about 5 million Americans, are wholesale loss of synapses - contact points via which nerve cells relay signals to one another - and a parallel deterioration in brain function, notably in the ability to remember.
"Our discovery suggests that Alzheimer's disease starts to manifest long before plaque formation becomes evident," said
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 connections between nerve cells. They are essential to storing memories, processing thoughts and emotions, and planning and ordering how we move our bodies. The relative strength of these connections, moreover, can change in response to new experiences.
Using an experimental mouse strain that is highly susceptible to the synaptic and cognitive impairments of Alzheimer's disease, Shatz and her colleagues showed that if these mice lacked a surface protein ordinarily situated very close to synapses, they were resistant to the memory breakdown and synapse loss associated with the disorder. The study demonstrated for the first time that this protein, called PirB, is a high-affinity receptor for beta-amyloid in its "soluble cluster" form, meaning that soluble beta-amyloid clusters stick to PirB quite powerfully. That trips off a cascade of biochemical activities culminating in the destruction of synapses.
Shatz is the Sapp Family Provostial Professor, as well as the director of Bio-X, a large
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