While LR11 expression is robust in the healthy brain, the expression of this low density lipoprotein receptor is drastically reduced in Alzheimer's disease (AD) brain. Moreover, LR11 is known to play a role in maintaining low levels of beta amyloid (A3), the peptide widely believed to play a critical role in the AD pathogenic cascade. Recent evidence has suggested that LR11 does this by regulating the the intracellular localization of the amyloid precursor protein (APP), which from which Ap is generated. Because different APP - processing enzymes are found in different sub-cellular compartments, altering where in the cell APP is found ultimately determines how much APP is cleaved into A(3. In light of this proposed role for LR11, we hypothesize that compounds that interact with LR11 through known ligand binding domains in the ectodomain of the receptor are capable of influencing the known effects of LR11 on Ap. In this study, we will use a basic cell culture system to characterize the effects of two known LR11 ligands on the trafficking and processing of APP, and to delineate the role of LR11 in mediating these reactions.
In Specific Aim 1, we will test the hypothesis that the small peptide head activator (HA) influences LR11 function an modulates APP processing.
In Aim 1 A, we will determine the effects of HA binding to LR11 on the processing APP and in Aim 1B, we will look at how LR11 mediates those effects, focusing on the altered trafficking of APP.
In Specific Aim 2, we will test the hypothesis that apoE influences LR11 function and modulates the trafficking of APP in an isoform dependent manner.
In Aim 2 A, we will focus on how apoE3 and E4 are able to direct the trafficking of LR11 and APP, and how these changes influence the processing of APP.
In Aim 2 B, we will look at how the effects of apoE2 binding to LR11 on APP trafficking and processing differ from those seen in response apoE4 and the mechanisms underlying these differences. These studies will better our understanding of the role of LR11 in the AD pathogenic cascade and in particular, its ability to regulate APP in the brain. Ultimately, this work will begin to lay the ground work that we believe will someday yield LR11 based - AD therapeutics.
| Sager, Kristen L; Wuu, Joanne; Herskowitz, Jeremy H et al. (2012) Neuronal LR11 expression does not differentiate between clinically-defined Alzheimer's disease and control brains. PLoS One 7:e40527 |
| Sager, Kristen L; Wuu, Joanne; Leurgans, Susan E et al. (2007) Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol 62:640-7 |
