Scientists crossbred mice that develop Alzheimer’s-like changes in the brain with mice genetically altered to make more of the low-density lipoprotein receptor (LDLR) in their brains. The resulting offspring had lower levels of amyloid beta, the protein fragment that clumps together to form amyloid plaques in Alzheimer’s disease.
“This suggests the intriguing possibility that some of the compounds and strategies now in development to treat heart disease, many of which boost LDLR levels to lower blood cholesterol, may one day be modified and adapted for use in Alzheimer’s disease,” says senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital.
Holtzman says researchers need more precise details of how LDLR affects amyloid beta levels to determine the best way to target that connection with pharmaceuticals in humans. But he believes testing compounds that promote LDLR function in animals with Alzheimer’s-like conditions could be useful to developing new therapies for Alzheimer’s disease.
The findings appear in the Dec. 10 Neuron.
LDLR has been of interest to cardiovascular researchers because it allows cells lining the circulatory system to decrease levels of low-density lipoprotein (LDL) cholesterol, sometimes referred to as bad cholesterol, in the bloodstream. This helps prevent LDL cholesterol from building into atherosclerotic plaques that lead to strokes and heart attacks.
Holtzman’s laboratory became curious about LDLR’s role in Alzheimer’s because it binds to apolipoprotein E (ApoE). A variation of the gene for this protein is the strongest inherited risk factor for late-onset Alzheimer’s disease. Discovery of this link provided scientists with an important lead into the knotty tangle of factors that may cause Alzheimer’s, but the details of ApoE’s exact role in the disease process remain to be worked out.
Part of the challenge has been that ApoE binds to several different receptors in the brain. In earlier studies, Holtzman and others showed that eliminating one such receptor in the brain, LDLR, increased ApoE levels but did not significantly affect plaque formation.
In the new study, first author Jungsu Kim, Ph.D., a postdoctoral fellow in Holtzman’s laboratory, reports that doubling normal levels of LDLR caused brain ApoE levels to drop by 50 percent. Higher increases in LDLR levels drove brain ApoE down as much as 85 to 90 percent.
Crossing mice that have increased LDLR in the brain with a mouse model of Alzheimer’s disease produced a line of mice with fewer amyloid plaques and less inflammation in the brain. When Joseph Castellano, a neuroscience graduate student in Holtzman’s lab, sampled the spaces between brain cells, he found reduced levels of amyloid beta.
“We think that LDLR’s ability to lower amyloid beta is a result of its effects on ApoE levels, but we haven’t proven that yet,” says Holtzman. “ApoE binds to amyloid beta, so one possibility is that ApoE and amyloid beta in a combined form are both being cleared from the brain when they bind to LDLR.”
It’s also possible that LDLR directly binds to amyloid beta and clears it from the brain, Holtzman says, or reduced levels of ApoE may make it harder for amyloid beta to aggregate into plaques. Holtzman’s group is studying these possibilities in the lab and in animal models.
Additional follow-up studies will assess the effects of increasing LDLR on cognitive function in the mice.
Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular amyloid beta clearance. Neuron, Dec. 10, 2009.
Funding from the American Health Assistance Foundation, the National Institutes of Health, the Alafi Neuroimaging Laboratory, and Eli Lilly supported this research.
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.