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Mechanism of Alzheimer's suggests combination therapy needed
Date:3/17/2009

tions to other nerve cells.

"We know from study of several hereditary adult-onset neurodegenerative diseases that damage to the transport system, over time, results in loss of synaptic activity, a gradual dying back of the neurons, and eventual neuron death -- exactly the pattern of Alzheimer's disease progression," Brady said.

"Neurons have an enormous logistical problem," Brady said. "Their critical role in making connections may require them to be very large. Some of them have to reach half the body's length -- for a tall person, a meter or more." Even just within the brain, he said, neurons are tremendously long compared to other cells.

The fast axonal transport system responsible for moving proteins and vesicles from the neuron's cell body where they are made, down the long, trunk-like projection of the axon, to the functional areas where they are needed and back again depends on motor proteins that attach to the cargo -- a vesicle or protein -- and carry it along a track made of microtubules.

In the new study, Brady and his colleagues showed that the short assemblies of amyloid activate a transport-regulatory enzyme called CK2 that causes the motor protein to drop its cargo. They were also able to show that inhibition of CK2 is sufficient to prevent the effects of amyloid on transport.

In the earlier work, the researchers showed that tau tangles halt transport to the neuron periphery through other regulatory enzymes by causing the motor protein to release the microtubule track.

The researchers found that the CK2 activated by amyloid also works as a primer for one of the enzymes activated by tau tangles, GSK3.

"Now we have the perfect storm," said Brady. "Both amyloid and tau tangles cause problems. But when you put them together, you exacerbate the problems, creating the cascade of events that cause Alzheimer's loss of neural connections.

"It makes sense of why both have to be present to
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Contact: Jeanne Galatzer-Levy
jgala@uic.edu
312-996-1583
University of Illinois at Chicago
Source:Eurekalert

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