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2007 Grant - Weisgraber
Association of ApoE4 With Alzheimer's Disease: A New Paradigm
Karl H. Weisgraber, Ph.D.
The J. David Gladstone Institutes
San Francisco, California
Candidate for 2007 Zenith Fellows Award
The APOE gene is the biological "blueprint" for a protein called apolipo-protein E, which is involved in the transport of lipids (fats) into cells. This gene occurs most commonly in three forms: APOE-e2, APOE-e3 and APOE-e4. The e4 variant is associated with a greater risk of Alzheimer's disease. The protein produced by this variant, apolipoprotein E-e4, appears to promote the degeneration of nerve cells and accelerate the onset of Alzheimer's. However, scientists know little about the biological mechanisms behind these actions.
Apolipoprotein E-e4 has several structural features that distinguish it from the other variants. One of these features, called domain interaction, is character-ized by the two ends of the protein binding together to form a compact molecule. Karl H. Weisgraber, Ph.D., and colleagues believe that this feature contributes to the closer association between Alzheimer's and apolipoprotein E-e4. To test their hypothesis, the researchers genetically engineered mice to produce apolipoprotein with domain interaction, or Arg-61 apolipoprotein. Analysis of the mice found that their brains actually had Arg-61 levels that were lower than the levels of normal apolipoprotein. Further testing found that helper cells called astrocytes, which secrete most of the brain's apolipopro-tein, were responsible for this discrepancy. The researchers observed that Arg-61-producing astrocytes secreted low levels of the protein variant. Other evidence indicated that Arg-61 astrocytes became stressed, and that this stress reduced their ability to support and maintain nerve cells. Such problems could lead to nerve cell damage and memory loss.
Collectively, these early results suggest that astrocytes play a previously unappreciated role in the link between APOE-e4 and Alzheimer's. For this proposed grant, Dr. Weisgraber's team will explore more thoroughly why Arg-61 astrocytes produce low levels of Arg-61 apolipoprotein. They also will examine how and why these astrocytes lose some of their ability to maintain nerve cells. Such work could lead to new therapeutic strategies to reverse the harmful effects of APOE-e4.