Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid β protein production via the β-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling
Increasing evidence suggests that the low density lipoprotein receptor-related protein (LRP) affects the processing of amyloid precursor protein (APP) and amyloid beta (Abeta) protein production as well as mediates the clearance of Abeta from the brain. Recent studies indicate that the cytoplasmic domain of LRP is critical for this modulation of APP processing requiring perhaps a complex between APP, the adaptor protein FE65, and LRP. In this study, we expressed a small LRP domain consisting of the C-terminal 97 amino acids of the cytoplasmic domain, or LRP-soluble tail (LRP-ST), in CHO cells to test the hypothesis that the APP.LRP complex can be disrupted. We anticipated that LRP-ST would inhibit the normal interaction between LRP and APP and therefore perturb APP processing to resemble a LRP-deficient state. Surprisingly, CHO cells expressing LRP-ST demonstrated an increase in both sAPP secretion and Abeta production compared with control CHO cells in a manner reminiscent of the cellular effects of the APP "Swedish mutation." The increase in sAPP secretion consisted mainly of sAPPbeta, consistent with the increase in Abeta release. Further, this effect is LRP-independent, as the same alterations remained when LRP-ST was expressed in LRP-deficient cells but not when the construct was membrane-anchored. Finally, deletion experiments suggested that the last 50 amino acid residues of LRP-ST contain the important domain for altering APP processing and Abeta production. These observations indicate that there are cellular pathways that may suppress Abeta generation but that can be altered to facilitate Abeta production.
"Stimulation of proteolysis depends on the cellular localization of APP, which is regulated by a complex protein network. The low-density lipoprotein receptor-related protein (LRP1), a member of the LDL receptor superfamily , is an endocytic receptor for APP and critically involved in APP processing and signaling     . APP and LRP1 are linked by the neuronal adapter protein Fe65   . "
[Show abstract][Hide abstract] ABSTRACT: Neuronal Fe65 is a central adapter for the intracellular protein network of Alzheimer's disease related amyloid precursor protein (APP). It contains a unique tandem array of phosphotyrosine-binding (PTB) domains that recognize NPXY internalization motifs present in the intracellular domains of APP (AICD) and the low-density lipoprotein receptor-related protein LRP1 (LICD). The ternary APP/Fe65/LRP1 complex is an important mediator of APP processing and affects β-amyloid peptide production. Here we dissect by biochemical and biophysical methods the direct interactions within the ternary complex and reveal a phosphorylation-dependent insulin receptor substrate (IRS-) like interaction of the distal NPVY(4507) motif of LICD with Fe65-PTB1.
"Furthermore it is well known that the Low Density Lipoprotein Receptor-Related Protein (LRP) not only physically associates with APP but also with β-integrins (Salicioni et al., 2004). We have shown that LRP promotes APP endocytosis and Aβ generation in lipid raft microdomains (Pietrzik et al., 2002; Yoon et al., 2005; Yoon et al., 2007). In addition, LRP is required to mediate the trafficking of β-integrins to the cell surface (Salicioni et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: The major defining pathological hallmarks of Alzheimer's disease (AD) are the accumulations of Aβ in senile plaques and hyperphosphorylated tau in neurofibrillary tangles and neuropil threads. Recent studies indicate that rather than these insoluble lesions, the soluble Aβ oligomers and hyperphosphorylated tau are the toxic agents of AD pathology. Such pathological protein species are accompanied by cytoskeletal changes, mitochondrial dysfunction, Ca(2+) dysregulation, and oxidative stress. In this review, we discuss how the binding of Aβ to various integrins, defects in downstream focal adhesion signaling, and activation of cofilin can impact mitochondrial dysfunction, cytoskeletal changes, and tau pathology induced by Aβ oligomers. Such pathological consequences can also feedback to further activate cofilin to promote cofilin pathology. We also suggest that the mechanism of Aβ generation by the endocytosis of APP is mechanistically linked with perturbations in integrin-based focal adhesion signaling, as APP, LRP, and β-integrins are physically associated with each other.
"This process involves the interaction of megalin's cytoplasmic tail domain with several adaptor and scaffold proteins (Biemesderfer, 2006; May et al., 2003), including Dab2, MAGI-I, GIPC, ANKRA, MegBP, and ARH (Bonifacino and Traub, 2003; Jaeger and Pietrzik, 2008). The adaptor protein FE65 has been shown to mediate the interaction between another member of the LDLR superfamily, the LRP1, and the amyloid precursor protein (APP) (Cam and Bu, 2006; Pietrzik et al., 2004; Yoon et al., 2005). Due to the growing evidence that megalin expression in the central nervous system is not restricted to tight-junction epithelia, but is also expressed in neurons, the objective of our study was to assess the expression of megalin in different subpopulations of neurons, explore the interaction between megalin, APP and FE65, and discuss its possible functional role in the central nervous system. "
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence has implicated megalin, a low-density lipoprotein receptor-related protein, in the pathogenesis of Alzheimer's disease (AD). In the brain, megalin is expressed in brain capillaries, ependymal cells and choroid plexus, where it participates in the clearance of brain amyloid β-peptide (Aβ) complex. Recently, megalin has also been detected in oligodendrocytes and astrocytes. In this study we demonstrate that megalin is widely distributed in neurons throughout the brain. Additionally, given that FE65 mediates the interaction between the low density lipoprotein receptor-related protein-1 and the amyloid precursor protein (APP) to modulate the rate of APP internalization from the cell surface, we hypothesize that megalin could also interact with APP in neurons. Our results confirm that megalin interacts with APP and FE65, suggesting that these three proteins form a tripartite complex. Moreover, our findings imply that megalin may participate in neurite branching. Taken together, these results indicate that megalin has an important role in Aβ-mediated neurotoxicity, and therefore may be involved in the neurodegenerative processes that occur in AD.
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