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2008 Grants - Bu
LRP1 and APOE Isoforms in Brain Lipid Metabolism and Synaptic Functions
Guojun Bu, Ph.D.
Mayo Clinic Jacksonville
St. Louis, Missouri
2008 Zenith Fellows Award
The APOE gene provides the biological "blueprint" for a protein called apolipoprotein E, which is involved in the transport of cholesterol and other lipids (fats) into cells. The gene occurs most commonly in three forms, APOE-e2, APOE-e3 and APOE-e4. Studies have found that the e4 variant is associated with a greater risk of acquiring late-onset Alzheimer's, the most common form of the disease. However, scientists know little about the biological mechanisms underlying the association between APOE-e4 and Alzheimer's.
In previous studies, Guojun Bu, Ph.D., and colleagues engineered mice to lack the gene for a protein called low-density lipoprotein receptor-related protein 1 (LRP1). These mice exhibited decreased levels of helpful brain lipids, as well as the loss of synapses—tiny gaps through which nerve cells send and receive messenger chemicals. The animals also showed reductions in memory, likely caused by the loss of synaptic function. Further research found that mice genetically engineered to produce APOE-e4 had lower levels of LRP1 than did mice engineered to produce APOE-e3. The APOE-e4 mice also suffered decreases in synaptic function and brain lipid levels.
For this proposed study, Dr. Bu's team will analyze more thoroughly how low levels of LRP1 lead to problems with lipid metabolism and synaptic function. They will engineer mice that 1) lack the LRP1 gene and 2) produce either APOE-e4 or APOE-e3. They will then compare the levels of synaptic function and lipid metabolism in these two groups of mice. The researchers hope to learn more about how APOE-e4 and APOE-e3 may regulate LRP1 differently. They also hope to learn whether or not high levels of LRP1 might help prevent synaptic loss, memory impairment and other hallmarks of Alzheimer's disease.