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Gladstone study reveals how genetic factor may increase risk for Alzheimer's disease

Researchers at the Gladstone Institute of Neurological Disease have identified processes that may explain how a key protein, apolipoprotein E4 (apoE4), contributes to the development of Alzheimer's disease. Their findings, described in the Journal of Neuroscience (March 10, 2004), include identifying where in the brain apoE4 is broken down into toxic fragments that can impair the function and survival of nerve cells. Results of their study may point the way to a new therapeutic strategy for the prevention and treatment of Alzheimer's disease.

ApoE4 is the best known genetic risk factor for Alzheimer's disease, but, until now, the mechanism by which it increases that risk has remained a mystery. The key finding of the current study relates to apoE4's tendency to be broken down into toxic fragments when it is produced in neurons, the brain cells responsible for cognitive functions.

Proteins can be broken into small pieces by enzymes known as proteases in a process termed proteolysis. While the degradation of proteins is important for many cell processes, it can be harmful when it occurs inappropriately, not only because it destroys the protein, but also because abnormally high levels of fragments can damage cells.

In the new study, involving the examination of genetically engineered mice, Gladstone researchers have established that:

  • only apoE4 produced by neurons is susceptible to fragmentation, unlike apoE4 produced by other brain cells;
  • fragmentation is correlated with age, occurring more frequently the older the animal, similar to the effect of age on Alzheimer disease risk in humans;
  • fragmentation of apoE4 occurs predominantly in the very parts of the brain that are most vulnerable to Alzheimer's disease, the neocortex and hippocampus. In contrast, fragmentation does not occur in the cerebellum, which is much less vulnerable to Alzheimer's disease;
  • the apoE4 fragments cause
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Contact: John Watson
jwatson@gladstone.ucsf.edu
415-695-3833
University of California - San Francisco
23-Mar-2004


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