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Dissertation
Calcineurin regulates APP metabolism: In vitro & In vivo studies
Doctor of Philosophy (Ph.D.), Drexel University
May 2013
DOI:
https://doi.org/10.17918/etd-6997
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disease determined by the combination of environmental and genetic factors. AD is pathologically characterized by the accumulation of amyloid-[beta] peptide (A[beta]) and intraneuronal neurofibrillary tangles. Production of the A[beta] peptide by the regulated intra-membrane proteolysis of the [beta]-amyloid precursor protein (APP) by the [alpha], [beta] and [gamma] secretase enzymes is the central biological pathway in AD. Cognitive decline observed in AD models is dependent on A[beta] generation. Of particular interest to the work presented here is the observation that APP proteolysis and levels of A[beta] can be regulated by phosphorylation and phosphorylation-dependent events. Downstream effects mediated by soluble A[beta] aggregates include hyperactivation of a calcium (Ca²⁺) and calmodulin (CaM)-dependent, serine-threonine protein phosphatase calcineurin (CaN). In our study we investigate the role of CaN in AD, and specifically its ability to regulate APP metabolism. CaN acts as heterodimer of CaNA (catalytic subunit) and CaNB (regulatory subunit) and its phosphatase activity can be inhibited using pharmacological drug FK506. Using genetic and pharmacological manipulation of CaN in SH-SY5Y cells and cortical neurons as in vitro models and [gamma]-secretase reporter fly and transgenic fly expressing human APP and BACE as our in vivo AD model (Chakroborty et al), we demonstrate that CaN regulates the proteolytic processing of APP. We also observe a decrease in A[beta] and AICD levels on inhibition of CaN phosphatase activity. Furthermore, CaN inhibition rescues the A[beta] dependent, AD-like behavioral and cognitive deficits observed in our transgenic fly AD model. Overall, our results demonstrate CaN inhibition may rescue cognitive and neurodegenerative effects of A[beta] by regulating APP proteolytic processing. Our work also lays the ground for designing better and more specific drugs that inhibit CaN activity and can act as a potential AD therapeutic.
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Details
- Title
- Calcineurin regulates APP metabolism
- Creators
- Suruchi Utreja - DU
- Contributors
- Kenneth Lacovara (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 214 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 6997; 991014632650904721