Ever since the ApoE4 allele was identified as a risk factor in late-onset Alzheimer's, researchers have speculated that ApoE interacts with β-amyloid. Several years ago, Kelly Bales and colleagues at Lilly Research Laboratories demonstrated the ApoE clearly affects deposition of beta amyloid. They did this by crossbreeding mice overexpressing mutant APP (which causes early-onset Alzheimer's in humans) with mice unable to make their own ApoE. These mice formed fewer amyloid deposits than did those with ApoE.
Now, in a new study, David Holtzman of Washington University School of Medicine "knocked in" the human ApoE gene into mice that had their own ApoE genes knocked out. Then he and his colleagues at Lilly crossbred them to the APP transgenic mice. Normally, the APP transgenics develop β-amyloid deposits in their brains by nine months of age. But those with human ApoE3 and E4 did not develop them until later. It is not yet known whether E3 and E4 lead to different amounts of deposition. "This is the first experiment that clearly demonstrates that human ApoE affects amyloid-β metabolism in vivo," says David M. Holtzman.
These findings are a bit paradoxical, because a similar effect is seen in APP transgenic mice that lack native ApoE. The difference between mouse and human ApoE may provide an important clue about the underlying mechanism by which ApoE affects APP metabolism. The researchers suggest that human ApoE might remove Aβ molecules out of incipient plaques the way it removes cholesterol out of atherosclerotic plaques in arteries. "This suggests the intriguing possibility that raising levels of ApoE might slow the onset or progression of Alzheimer's disease," Holtzman says.—June Kinoshita
Listen to Dr. Holtzman's Keystone Symposium presentation. Note: To listen to this presentation, you will need to download and install RealPlayer 5.0. This version of RealPlayer is free.
No Available Further Reading
- Holtzman DM, Bales KR, Wu S, Bhat P, Parsadanian M, Fagan AM, Chang LK, Sun Y, Paul SM. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J Clin Invest. 1999 Mar;103(6):R15-R21. PubMed.