Beta-amyloid precursor protein (Beta-APP) is an integral transmembrane glycoprotein whose proteolytic processing results in the generation and secretion of soluble Beta-APP amino-terminal peptides (sBeta-APP) as well as amyloid-beta protein (A-Beta), the major constituent of the amyloid deposited in the brain of Alzheimer's disease patients. The protein interaction domain of two adaptor proteins, X11 and Fe65, bind to the YENPTY motif within the cytoplasmic domains of Beta-APP. Since this motif has a role in the internalization of Beta-APP, and A-Beta is generated in part following Beta-APP internalization, the effect of X11 and Fe65 binding on Beta-APP trafficking and processing have been studied. It was hypothesized that A-Beta and sBeta-APP are physiological ligands with reciprocal effects on neuronal integrity, and imbalance in the relative amounts of A-Beta and sBeta-APP may have beneficial or deleterious effects on neuronal survival and growth. The goal of this application is to test the hypothesis that complexes among the adaptor proteins and Beta-APP reflect a signaling pathway that regulates the processing of Beta-APP. Specifically, Aim 1 is to examine the effect of Fe65 binding to Beta-APP on Beta-APP processing and secretion and to compare this effect to that of X11;
Aim 2 is to examine the effect of X11 and Fe65 binding to Beta-APP on cell associated Beta-APP trafficking;
Aim 3 is to establish a transgenic mouse model overexpressing human X11 in the formation and deposition in transgenic mice overexpressing human X11 in the brain;
and aim 4 is to examine the effect of X11 association with Beta-APP on A-Beta secretion and on amyloid formation and deposition in transgenic mice overexpressing both X11 and Beta-APP. Study of the molecular function of Beta-APP within a signal transduction pathway may lead to insights on pathological processes activated or inhibited in Alzheimer's disease patients. Manipulating the interaction of Beta-APP with an effector protein, such as X11 or Fe65, may provide a novel approach for the pharmacological modulation of Beta-APP processing in Alzheimer's disease.
| Levy, Efrat; Prelli, Frances; Frangione, Blas (2006) Studies on the first described Alzheimer's disease amyloid beta mutant, the Dutch variant. J Alzheimers Dis 9:329-39 |
| Pawlik, Monika; Sastre, Magdalena; Calero, Miguel et al. (2004) Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid Beta Peptide. J Mol Neurosci 22:13-8 |
