ROLE OF HFE65 PROTEINS IN ALZHEIMER'S DISEASE.
Principal Investigator: SUZANNE Y GUENETTE
Affiliation: Harvard University
Abstract: DESCRIPTION (From the applicant's abstract): Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline due to selective neuronal degeneration and synaptic loss in regions of the brain where spatial learning and memory are consolidated. Pathogenic events including the generation and deposition of the neurotoxic 4kDa peptide, Abeta, are believed to cause neuronal loss in AD. Both the neurotoxic Abeta peptide and the neuroprotective APPs are generated from APP within the secretory pathway. Furthermore, Abeta is also generated within the endocytic pathway. The cellular events that modulate the ratios of APPs and Abeta isoforms are not fully understood. The complexity of these events is illustrated by the recent observations that the Abeta isoforms prominently associated with AD, Abeta 40 and Abeta 42, are produced at distinct subcellular sites. Therefore, studying proteins that may directly or indirectly modulate APP trafficking and processing is relevant to AD. Because of their demonstrated interaction with the YENPTY trafficking signal of the APP, the FE65L and X11 proteins deserve further study. Our published results indicate that overexpression of FE65L increases secretion of APP-s-alpha in H4 neuroglioma cells. In addition, increased Abeta secretion due to FE65 overexpression has been reported. Furthermore, FE65 has recently been shown to bind LRP. Our preliminary results indicate that FE65L binds LRP and decreases steady state levels of LRP when overexpressed in H4 neuroglioma cells. We propose to study the FE65L-APP interaction and its relevance to AD by asking the following questions: Is the binding of FE65L to APP required for its effect on APPs and Abeta secretion? Does the binding of hFE65L to LRP contribute to the extracellular pool of APPs and Abeta? Does the FE65L-APP interaction have an effect on intracellular Abeta42 production? Does FE65L act as an adaptor protein form a tripartite complex with APP and LRP?
Funding Period: 2000-09-01 - 2005-05-31
more information: NIH RePORT