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A Jekyll-and-Hyde enzyme's role in Alzheimer's

Researchers have discovered how a brain enzyme important in the development and maintenance of learning and memory also plays a key role in the death of neurons in neurodegenerative disorder such as Alzheimer's disease (AD). They found that the enzyme's transformation from Jekyll to Hyde may be due to abnormal activation of the brain's mechanism to compensate for the damage from such diseases. This compensatory mechanism may also function in normal aging, they said.

In their article in the December 8, 2005, issue of Neuron, Li-Huei Tsai and colleagues said their findings in mice could offer a model to study how normal neural mechanisms can go awry to contribute to the brain degeneration of AD.

The researchers' studies concentrated on a key brain regulatory enzyme called Cdk5. Elevated levels of Cdk5 had been found in the brains of AD patients, as well as elevated levels of a regulatory protein called p25 that is known to hyperactivate Cdk5. Researchers had found that the hyperactivating p25 is produced when the normal regulatory protein for Cdk5, called p35, is snipped into the shorter p25 by another enzyme.

In their experiments, the researchers used mice in which they could switch on p25 at will in the brain's learning and memory center, the hippocampus. In these mice, they found that switching on p25 for only two weeks actually enhanced learning and memory compared to normal mice. The two-week p25 mice could learn more quickly to associate a tone or environment with a mild electrical shock and to find a platform submerged in a pool of murky water.

In contrast, found the researchers, mice in which p25 had been switched on for six weeks showed impaired learning and memory in these tasks. Physiological studies showed that these mice showed significant brain atrophy and loss of hippocampal neurons. The researchers also showed that the two-week pulse of p25 did not cause neurodegeneration and had long-lasting effects on enhancing memory.
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
7-Dec-2005


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