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Caloric restriction and SirT1 modulate APP metabolism in vitro and in vivo
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http://hdl.handle.net/1860/3207
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| Title: | Caloric restriction and SirT1 modulate APP metabolism in vitro and in vivo |
| Authors: | Chakraborty, Ranjita |
| Keywords: | Biology
Molecular biology
Biochemistry |
| Issue Date: | 30-Mar-2010 |
| Abstract: | Proteolytic processing of the β-amyloid precursor protein (APP) by α-, β-and γ-secretase enzymes generating the amyloid-beta (Aβ) peptide and the APP intracellular domain (AICD) is a central event in Alzheimer’s disease (AD). Herewe show that in vitro CR decreases Aβ, AICD and full-length APP levels in human cell lines without affecting APP transcription and that some of these effects can be recapitulated by over-expressing the NAD+ dependent deacetylase SirT1 in our cell lines. Resveratrol, a SirT1 agonist, also has similar effects on APP metabolism. SirT1 and resveratrol however, do not affect full-length APP levels. In our cell lines, SirT1and resveratrol reduces secreted Aβ levels by increasing the α-secretase cleavage of APP and also possibly by affecting γ-secretase activity. Extending these studies to an in vivo setting, an AICD reporter Drosophila model of AD, shows that caloric restriction, Sir2 gain-of-function and resveratrol treatment suppress AD-like rough-eye phenotype in the fly eyes. Finally to study the mechanism of CR and SirT1 mediated effects on APP metabolism in entire central nervous system, we created and characterized a novel Drosophila model of AD. We have shown that our model displays neuroanatomical and behavioral features that are characteristic of AD patients. |
| URI: | http://hdl.handle.net/1860/3207 |
| Appears in Collections: | Drexel Theses and Dissertations
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