THE ROLE OF ENDOSOMAL COMPARTMENTS IN ALZHEIMER’S DISEASE
J.J. Lah and A.I. Levey
Department of Neurology
Emory University
1639 Pierce Drive
Atlanta, GA 30322
Recent advances in our understanding of the molecular events underlying Alzheimer’s disease (AD) have identified new targets for therapeutic intervention and generated hopes for truly effective treatments for this devastating illness. Many of these approaches are designed to reduce the production or enhance the clearance of the amyloid beta-peptide (A-beta) which is the primary component of senile plaques found in the brains of AD patients. A-beta is produced through a series of enzymatic processing events which cleave the amyloid precursor protein (APP) by alternative pathways leading to production of either A-beta or a non-toxic peptide, P3. An important aspect of APP processing involves cell biological mechanisms which control its movement to specific intracellular compartments. This control of APP trafficking likely plays a critical role in regulating its exposure to enzymes which mediate production of either A-beta or P3, and, thus, may represent additional targets for primary or adjunctive therapies.
The goal of the studies presented here is to define the relevant intracellular sites for APP processing and identify control mechanisms which regulate APP trafficking to these compartments. We have focused these studies on the examination of endosomal compartments in cultured cells and rodent brains. APP is known to traffic through the endocytic pathway, and endosomes have previously been identified as a major site of A-beta production. For these studies, endosomes were identified based on the presence of molecular markers which define endosomal compartments, including transferrin receptor, Rab5, and Rab11. In other cases, horseradish peroxidase was used as a nonspecific marker for fluid-phase endocytosis. The presence of these markers was used in immunocytochemical, immunoisolation, and subcellular fractionation studies to demonstrate the presence of APP and its processed derivatives in early endosomes. In addition, proteins which are involved in A-beta production, presenilin-1 (PS1) and BACE, were also localized to early endosomes, suggesting that they may interact with APP within these compartments. In another series of experiments, APP trafficking through early endosomes was manipulated through the expression of mutant Rab5 molecules which modify membrane fusion events in early endosomes. The results of these studies suggest that Rab5-positive early endosomes may be a key compartment for APP-PS1 interaction and production of A-beta. We are now investigating pharmacologic agents which may modify APP processing and A-beta production by altering normal trafficking patterns through the endocytic pathway. These studies should continue to improve our understanding of the cell biological mechanisms involved in AD and identify novel targets for therapeutic intervention.
Supported by NIH-NINDS (NS01902), AFAR/Pfizer Research Grant, and SCEGM/Hartford Foundation.
Key words:
Alzheimer's, Cell Biolgy, Amyloid, Presenilin, BACE
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