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Response to Correspondence: Pardossi-Piquard et al., “Presenilin-Dependent Transcriptional Control of the Aβ-Degrading Enzyme Neprilysin by Intracellular Domains of βAPP and APLP.” Neuron 46, 541–554

University of Toronto, Toronto, Ontario, Canada
Neuron (Impact Factor: 15.98). 03/2007; 53(4):483-6. DOI: 10.1016/j.neuron.2007.01.024
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    • "Specifically, work by De Strooper and colleagues (Hebert et al., 2006) has shown that expression of several previously defined AICD targets genes was at best indirectly and weakly affected by APP processing. Further, the role of AICD in regulating neprilysin expression (Pardossi-Piquard et al., 2005;Pardossi-Piquard et al., 2007) was not reproduced by another report (Chen and Selkoe, 2007). Finally, a recent study has shown that secreted APP ectodomain APPsα is sufficient to rescue several anatomical, behavioral, and electrophysiological abnormalities seen in APP-KO mice (Ring et al., 2007). "
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    ABSTRACT: Mutations in the amyloid precursor protein (APP) cause early-onset Alzheimer's disease (AD), but the only genetic risk factor for late-onset AD is the varepsilon4 allele of apolipoprotein E (apoE), a major cholesterol carrier. Using Cre-lox conditional knockout mice, we demonstrate that lipoprotein receptor LRP1 expression regulates apoE and cholesterol levels within the CNS. We also found that deletion of APP and its homolog APLP2, or components of the gamma-secretase complex, significantly enhanced the expression and function of LRP1, which was reversed by forced expression of the APP intracellular domain (AICD). We further show that AICD, together with Fe65 and Tip60, interacts with the LRP1 promoter and suppresses its transcription. Together, our findings support that the gamma-secretase cleavage of APP plays a central role in regulating apoE and cholesterol metabolism in the CNS via LRP1 and establish a biological linkage between APP and apoE, the two major genetic determinants of AD.
    Neuron 11/2007; 56(1):66-78. DOI:10.1016/j.neuron.2007.08.008 · 15.98 Impact Factor
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    • "AICD, together with its binding partners Fe65 and Tip60, is considered to be involved in transcriptional regulation (Cao and Sudhof, 2001). Putative target genes of AICD signaling have been suggested (Baek et al., 2002; Kim et al., 2003; von Rotz et al., 2004; Pardossi-Piquard et al., 2005; Ryan and Pimplikar, 2005; Muller et al., 2007), although results for some of these genes are controversial (Hass and Yankner, 2005; Hebert et al., 2006; Chen and Selkoe, 2007; Pardossi-Piquard et al., 2007). One potential AICD target gene is the A␤-degrading enzyme neprilysin (Pardossi-Piquard et al., 2005, 2006), a metalloprotease that is one of the main A␤-degrading enzymes in the brain (Carson and Turner, 2002). "
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    ABSTRACT: Amyloid-beta (Abeta) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Abeta secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Abeta levels without the inhibition of Notch cleavage by a mechanism distinct from gamma-secretase inhibition. Gleevec does not influence gamma-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Abeta is decreased. This effect is observed even in presence of a potent gamma-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Abeta-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Abeta-lowering effect may be caused by increased Abeta-degradation.
    Molecular Biology of the Cell 10/2007; 18(9):3591-600. DOI:10.1091/mbc.E07-01-0035 · 4.55 Impact Factor
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    ABSTRACT: Epidemiological studies suggest that a high intake of polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), is associated with a reduced risk of Alzheimer's disease. Here, we examined the effects of DHA on amyloid precursor protein (APP) processing in cellular models of Alzheimer's disease by analysing levels of different APP fragments, including amyloid-beta (Abeta). DHA administration stimulated non-amyloidogenic APP processing and reduced levels of Abeta, providing a mechanism for the reported beneficial effects of DHA in vivo. However, an increased level of APP intracellular domain was also observed, highlighting the need to increase our knowledge about the relevance of this fragment in Alzheimer's disease pathogenesis. In conclusion, our results suggest that the proposed protective role of DHA in Alzheimer's disease pathogenesis might be mediated by altered APP processing and Abeta production.
    European Journal of Neuroscience 09/2007; 26(4):882-9. DOI:10.1111/j.1460-9568.2007.05719.x · 3.67 Impact Factor
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