application) An invariant feature in the brain of patients with AD is the extraneuronal deposition of a specific amyloidogenic peptide derived from a transmembrane glycoprotein, the amyloid precursor protein, that is enriched within the neuronal compartment and whose function in the central nervous system is essentially unknown. The long-term goal of this research is to gain further insight into the molecular pathogenesis of AD by delineating the function(s) of the amyloid precursor protein (APP) in neurons. The protein may function as a cell-surface receptor that undergoes receptor-mediated endocytosis, and may also play a role in axonal guidance and synaptogenesis during neural development. The investigator will look at both of these functional issues, but this proposal will only address the issue of the APP and neuronal endocytosis. Recent evidence derived principally from non-neuronal systems suggests that cell- surface APP enters the endocytotic pathway and undergoes proteolytic processing to generate potentially amyloidogenic fragments. A general feature of endocytotic compartments is the ability to generate an acidic internal (luminal) environment, and this acidification plays an important role in the sorting and proteolytic processing of internalized transmembrane receptors and their respective macromolecular ligands. The investigator will use predominantly morphologic methods to assess the distribution and trafficking of the APP within endocytotic compartments of the axonal and somatodendritic domains in cultured central nervous system neurons, with particular emphasis on the role of vacuolar acidification in the trafficking and proteolytic processing of this protein. These studies may result in a detailed map of the routes by which central neurons internalize, sort and partially degrade this protein, and this map may serve to identify potential sites for pharmacologic intervention to inhibit cerebral amyloidogenesis and thus minimize cognitive decline in patients with AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AG000681-04
Application #
2683086
Study Section
Neuroscience, Behavior and Sociology of Aging Review Committee (NBSA)
Project Start
1995-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611