Scientists at the Stanford University School of Medicine have shown how a protein fragment known as beta-amyloid（淀粉体）, strongly implicated in Alzheimer's disease, begins destroying synapses（突触） before it clumps into plaques that lead to nerve cell death. 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 Carla Shatz, PhD, professor of neurobiology and of biology and senior author of a study that will be published Sept. 20 in Science.

Investigators at Harvard University also contributed to the study. The research, conducted in mice and in human brain tissue, may help to explain the failures in recent years of large-scale clinical trials attempting to slow the progression of Alzheimer's by pharmacologically ridding the brain of amyloid plaques. It may also point the way to better treatments at earlier stages of the disease.

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 Stanford interdisciplinary（各学科间的） consortium drawing on medical, engineering and biology faculty. She has been studying PirB for many years, but in a different context. In earlier work, Shatz explored the role of PirB in the brain using genetically engineered mice that lacked it. She discovered that PirB, previously thought to be used only by cells in the immune system, is also found on nerve cells in the brain, where it slows the ability of synapses to strengthen in proportion to the extent to which they are engaged, and actually promotes their weakening. Such brakes are desirable in the brain because too-easy synaptic strength-shifting could trigger untoward consequences like epilepsy.