Role of LRP in APP Catabolism and Generation of Amyloid Beta

Alzheimer disease is a neurodegenerative disorder that is characterized by extracellular deposits of insoluble aggregates in the brain. Analysis of these aggregates revealed that they are composed of a small molecule that has been termed the Aß peptide. Studies have found that this molecule is highly toxic to neurons. The AP peptide is generated when a much larger protein, called amyloid ß-precursor protein (APP), is digested by enzymes. These observations, along with the findings that APP is genetically linked to Alzheimers disease, have led to intensive study of the events that cause the generation of the AP peptide. Thus, the Aß peptide is a key molecule in Alzheimers disease, an understanding of how this peptide is generated is of great importance. APP is a large molecule that is embedded within the cell membrane. The Aß peptide represents a small fragment of APP. A large number of studies have been conducted with the goal of understanding how this small peptide is generated from the parent APP molecule. When APP is made, it is first delivered to the outer plasma membrane of the cell. At this location an enzyme, which has not yet been identified, can cleave APP within the region containing the Aß peptide. This cleavage releases the bulk of the molecule from the cell, and importantly, generates a molecule that can no longer produce the Aß peptide. The APP molecules that are not cleaved and released from the outer membrane of the cell are transported into the cell by a process that is called endocytosis. Once inside the cell, APP is quickly delivered to a compartment that contains digestive enzymes. It is in this compartment that the remaining two important cleavages of APP take place to generate the Aß peptide. Once the peptide is generated by digestive enzymes, it is transported back to the cell membrane and released from the cell. The objective of this application is to understand how APP is transported from the cell membrane into digestive compartments where enzymes reside that are responsible for generating the AP peptide. We think that transport molecules exist on the cell membrane that help carry APP into the compartments containing the digestive enzymes. This notion was prompted by our discovery that APP can bind to another molecule that is also found in the outer cell membrane. This molecule, termed LRP, is a protein that is capable of binding to a vast array of molecules and efficiently transporting them to compartments within the cell containing the digestive enzymes. The central hypothesis of this application is that LRP can also interact with APP in the outer cell membrane, and assist in transporting it to the digestive-enzymes within the cell where the Aß peptide is produced. The specific hypotheses to be tested are: 1) That LRP can bind and facilitate the transport of APP from the outer cell membrane to compartments containing the digestive enzymes 2) that this process effects the production of Aß peptide, and 3) that we can developed molecules to inhibit this process.