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2012 Grants - Kim
Regulation of LDLR as Alzheimer's Disease Therapeutics
Jungsu Kim, Ph.D.
St. Louis, Missouri
2012 New Investigator Research Grant
The protein fragment beta-amyloid, a key suspect in Alzheimer's disease, is clipped from a "parent" molecule called amyloid precursor protein (APP). Beta-amyloid tends to accumulate into toxic clumps within the Alzheimer's brain, hindering the ability of brain cells to communicate with one another and promoting brain cell death. Currently, the only well-established genetic risk factor for Alzheimer's is the gene variant APOE-e4. All APOE variants produce a protein called apolipoprotein-E, which helps transport lipids (fats) into cells. Research has found that changes in brain apolipoprotein levels are linked to beta-amyloid accumulation and other Alzheimer's pathologies—such as the brain accumulations of abnormal tau protein and the protein fragment beta-amyloid. Yet scientists do not know exactly why the APOE gene—and specifically the e4 variant—may generate abnormal amounts of its protein.
Jungsu Kim, Ph.D., and colleagues have been studying a "binding site" on APOE called the low-density lipoprotein receptor (LDLR). This protein enables APOE to interact with other molecules. The team found that LDLR can (1) regulate the production of apolipoprotein from the APOE gene and (2) regulate the production of beta-amyloid from APP. Dr. Kim's group hypothesizes that LDLR levels decrease as people age. This lost LDLR can lead to altered levels of apolipoprotein E and higher levels of toxic beta-amyloid in the elderly brain. Thus it is important to find compounds that are responsible for age-related LDLR losses. One such compound, called the inducible degrader of LDLR (IDOL), has already been identified, and Dr. Kim's group has recently found two other proteins that interact with IDOL.
For this grant, the researchers will test whether modifying the activity of their IDOL-interacting proteins can affect apolipoprotein and beta-amyloid levels in Alzheimer's-like mice. Such work could shed new light on how APOE promotes beta-amyloid toxicity. It could also lead to novel Alzheimer's drug therapies.