Functional Analysis of APPFE65 Interaction
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About the Research Project
Program
Award Type
Standard
Award Amount
$200,000
Active Dates
April 01, 1997 - March 31, 1999
Grant ID
A1997005
Summary
A prominent feature of Alzheimer’s disease (AD) neuropathology is the accumulation of ß-amyloid in the form of senile plaques and cerebral blood vessel deposits in the brain. The chief component of Alzheimer-associated ß-amyloid deposits is a peptide called Aß. Aß is derived from a larger protein called the amyloid ß protein precursor (ßPP). One form of Aß, Aß42, is particularly prone to ß-amyloid formation. Increased production of Aß42 has now been associated with pathogenic mutations in three different genes associated with early-onset ( years) familial Alzheimer’s disease (FAD); ßPP, presenilin 1, and presenilin 2. The accelerated deposition of Aß and Aß42 has prompted intensive investigations of how ßPP is processed in the cell under both normal conditions and in the presence of FAD gene defects. In these studies, emphasis has been placed on how Aß and Aß42 are generated and a critical finding has shown that the internalization or “recycling” of APP from the cell surface is necessary for the subsequent production of Aß. Accordingly, a great deal of attention has been placed on identifying the factors and cell mechanisms involved in ßPP trafficking and internalization. This proposal is aimed at continuing our ongoing efforts to identify and characterize factors and molecular interactions that may be involved in the trafficking, processing, and function of ßPP. In our initial funding period, we successfully employed the “interaction trap” to identify and characterize two novel proteins that interact with ßPP and the ßPP-Iike proteins (APLPs). In the current proposal, we have now chosen to focus on a novel family of human proteins called the human FE65 (hFE65) proteins. We have found that a member of this family differentially interacts with ßPP and the APLPs. The decision to focus on the hFE65 proteins was prompted by our findings that one member of this family, hFE65L, binds to endogenous ßPP in mammalian cells apparently via its interaction with a so-called “NPXY” motif in the cytoplasmic portion of ßPP. Since the NPXY motif has also been shown to be the site used for cellular internalization/recycling of ßPP, we have hypothesized that hFE65L and its family members may be able to regulate the rate at which ßPP is internalized. According to the available data, the rate of ßPP internalization would in turn be expected to impact on the rate of Aß production. Thus, the ultimate goal of the proposed studies is to further investigate the nature of the interactions between hFE65L and its human homologues with the ßPP/APLP family, to characterize the three members of the hFE65 family, and to investigate the effects of these novel proteins on the internaliz.ation of ßPP and Aß release. Studies of the interactions between members of the hFE65 and ßPP/ APLP families may also yield new insights into the normal cellular roles of these proteins. Interestingly, members of the hFE65 family contain specific functional domains which suggest possible roles for these proteins in transcriptional regulation and signal transduction. Thus, as part of the proposed studies, we will also endeavor to identify other proteins that interact with the hFE65 proteins. In this way, we hope to further elucidate the biological roles of these proteins, and by association, those of the ßPP/APLP family. Finally, we have mapped the hFE65L gene to human chromosome 3. In separate studies, we have recently generated significant genetic evidence indicating the existence of a novel late-onset FAD locus on chromosome 3. Consequently, we will sequence the hFE65L and other hFE65 genes to screen for potentially pathogenic mutations in our chromosome 3-linked as well as genetically unlinked FAD families. With regard to novel potential treatments for AD, it has been suggested that therapies targeted at regulating the cellular trafficking and processing of APP in a manner that reduces the production of Aß or Aß42 could be particularly useful for treating AD. The development of such therapies would require detailed knowledge regarding the cellular factors and mechanisms which regulate the processing of ßPP and information about the normal biological role of ßPP. The experiments proposed in the current application are aimed at expanding upon our discovery that the human FE65 proteins interact with ßPP and based on the nature of this interaction are strong candidates for governing the internalization of ßPP and the subsequent generation of Aß. Meanwhile, an elucidation of the function of the human FE65 proteins is very likely to shed new light on the normal cellular roles of ßPP and its human homologues.
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