Potential Alzheimer’s Therapy Targets Faulty APOE to Clear Brain Plaques
Alzheimer disease (AD) is the most common form of dementia and it affects more than 5 million people in the United States. Compelling evidence has shown that amyloid β (Aβ) plays a key role in the pathogenesis of AD.
The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). Previous studies have shown that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown.
Now, researchers at Washington University School of Medicine have shown that an antibody not only targets APOE for removal but sweeps away plaques.
“Many people build up amyloid over many years, and the brain just can’t get rid of it,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “By removing plaques, if we start early enough, we may be able to stop the changes to the brain that result in forgetfulness, confusion and cognitive decline.”
Fan Liao, Ph.D., and colleagues examined the molecular mechanisms underlying the finding that apoE influences Alzheimer’s disease
in part by affecting amyloid β (Aβ) aggregation and clearance.The authors examined whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and they also examined the underlying mechanisms. A model comprising APPPS1-21 mice crossed to apoE4 knockin mice expressing human apoE4 (APPPS1-21/APOE4) was used.
For six weeks, the mice were given weekly injections of placebo or antibodies against APOE. Then, the researchers measured the amount of plaques in their brains. One antibody – called HAE-4 – cut the level of plaques by half.
Moreover, HAE-4 had no effect on APOE levels in the blood. APOE plays an important role in transporting fats and cholesterol in the body, so removing it from the bloodstream could create unwanted side effects. The failure of the antibody to lower levels of APOE in the blood was therefore a good sign. But it was also a mystery. Why did the antibody clear APOE from the brain but not the blood?
“It turns out that the APOE in the plaques has a different structure than the form of APOE found in the blood,” Holtzman said. “The HAE-4 antibody recognized only the form found attached to the plaques in the brain.”
“The anti-amyloid antibodies are going to be binding to most of the molecules that are in the plaque, but the anti-APOE antibody would target just a very small component of the plaque,” Holtzman said. “This means we may find less immune activation, and we might not see the unwelcome side effects.“
