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Dissertation
Caloric restriction and SirT1 modulate APP metabolism in vitro and in vivo
Doctor of Philosophy (Ph.D.), Drexel University
Feb 2010
DOI:
https://doi.org/10.17918/etd-3207
Abstract
Proteolytic processing of the [beta]-amyloid precursor protein (APP) by [alpha]-, [beta]-and [gamma]-secretase enzymes generating the amyloid-beta (A[beta]) peptide and the APP intracellular domain (AICD) is a central event in Alzheimer's disease (AD). Herewe show that in vitro CR decreases A[beta], 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 A[beta] levels by increasing the [alpha]-secretase cleavage of APP and also possibly by affecting [gamma]-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.
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Details
- Title
- Caloric restriction and SirT1 modulate APP metabolism in vitro and in vivo
- Creators
- Ranjita Chakraborty - DU
- Contributors
- Aleister Saunders (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 3207; 991014632382504721