This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease (AD) is definitively diagnosed neuropathologically by the presence of senile plaques and neurofibrillary tangles in the limbic and association cortices. The predominant component of the extracellular senile plaque is amyloid beta (A-beta), a 39- to 43-amino acid peptide that is proteolytically derived from amyloid precursor protein (APP). The neuronal function of this ubiquitously expressed protein has not yet been elucidated. Although the pathogenetic mechanism(s) of AD remain to be determined, genetic, histopathologic, and biochemical evidence from humans, cell lines, and animal models implicates A-beta as a key factor in the neurodegenerative process. Therefore, one of the most prominent approaches in therapeutic development is to decrease A-beta production by inhibiting the secretases that release this peptide from APP.
The aim of this project is to extend the characterization of APP, to elucidate its normal role(s) and to understand how inhibiting the secretases may affect its physiologic function(s). Candidate binding partners have been crosslinked to full-length, plasma membrane APP stably expressed by human embryonic kidney 293 cells (HEK293). Two APP-containing complexes have been detected (Western blot, silver stain); proteomic approaches have resulted in identification of the constituent proteins. Identification of the binding partner(s) should have been straightforward, but characterization of this complex is difficult as HEK293 APP has two isoforms (751 and 770 amino acids) and is extensively glycosylated. A manuscript describing the results is now in press in the Journal of Neuroscience Research.
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