Project DetailsAlzheimer's disease (AD) is a progressive and irreversible disease of the brain leading to deterioration of mental function and eventual morbidity and death. The major defining characteristic of AD brains is the excessive accumulation of amyloid plaques, composed of a sticky protein called amyloid b (Ab). Ab is toxic to nerve cells, and this may explain the progressive degeneration seen in AD brains. Ab is formed when 'molecular scissors' cut APP into 2 places, resulting in the release of Ab. This is a normal process that also occurs in healthy individuals. However, for reasons we do not understand at present, Ab is either excessively produced or not removed fast enough in AD patients. One obvious way to block Ab formation is to inactivate the 'molecular scissors'. However, these proteins also have other important functions, such that blocking the 'molecular scissors' can have undesirable side effects. An alternative and perhaps additive design might be to block APP transport inside nerve cells so that it does not reach the sites where the 'molecular scissors' reside and are most active. In our studies, we found that a protein called LRP normally promotes Ab generation by directing the transport of APP inside cells to compartments where the 'molecular scissors' are most active. More than 80% of Ab production is dependent on the presence of LRP. Remarkably, we found that a very small region of LRP (LRP-C37) by itself is sufficient to mimic LRP in robustly increasing Ab generation. In addition, we identified new proteins that physically interact with the C37 domain and modify the cuts made in APP. At present, how LRP-C37 by itself or in the context of the full protein increases Ab production is not known. Furthermore, it is not known how the two new proteins we identified alter APP processing and Ab generation. We hypothesize that the LRP-C37 domain plays a critical role in transporting LRP and APP to compartments where Ab is normally generated. In this application, we propose to characterize the mechanistic basis of the LRP-C37 domain in LRP and APP transport inside cells and Ab generation. In addition, we will determine the role of the two new LRP-C37 interacting proteins in these processes. These studies are expected to form the basis of designing a novel therapeutic approach to block Ab generation.