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P2‐322: In vitro caloric restriction induces SIRT1 to modulate APP metabolism
Author(s) -
Chakraborty Ranjita,
Bowser Kathryn,
Zhang Can,
Pagano Daniel,
Pontano Laura,
Patel Neha,
Cueller Trinna,
Marenda Daniel,
Lee Jeremy,
Saunders Aleister
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1399
Subject(s) - calorie restriction , in vitro , sirtuin 1 , biology , microbiology and biotechnology , in vivo , metabolism , amyloid (mycology) , neurodegeneration , caloric theory , regulator , amyloid precursor protein , gene silencing , chemistry , downregulation and upregulation , biochemistry , endocrinology , alzheimer's disease , medicine , genetics , disease , gene , botany
Background: Caloric restriction (CR) is the only non-genetic method to “slow” aging and increase lifespan in mammals. CR (a 40% reduction in the total number of calories) “slows” aging by increasing the survival of critical cell types against a variety of stressors. Advanced age is the largest risk factor for developing Alzheimer’s disease (AD). In AD, there is a large loss of neurons. The molecular events that lead to this neuronal loss are dependent on proteolytic processing of the amyloid precursor protein (APP). APP processing can lead to the generation of the A peptide which is neurotoxic.In model organisms, the effects of caloric restriction on aging is mediated by the NADdependent deacetylase, Sir2 or SirT1 (Silencing Information Regulator) in humans. Methods: Here we are investigating if CR modulates the production of A thereby reducing the AD associated neuronal loss. Here we utilize an established cell culture model that recapitulates the major cellular phenotypes of CR. We find that in this in vitro CR model, A levels and APP metabolism are decreased due to CR treatment. To determine if SirT1 activity modulates APP metabolism in vivo, we utilized an established Drosophila model of AD. Results: Our findings suggest that effects of caloric restriction on A accumulation and APP metabolism may be dependent on the deacetylase activity of SirT1. Exposure of these cells to in vitro CR conditions results in an increase in SirT1 levels. We show here for the first time that in vitro CR decreases full-length APP levels also by SirT1 induction. We further show that Drosophila Sir2 over-expression decreases the AD phenotype of these flies, while Sir2 loss-of-function mutations enhance the fly AD phenotype. Conclusions: Our study suggests that in vitro caloric restriction decreases APP metabolism by inducing SirT1. These results are confirmed in our Drosophila model of AD. P2-323 MEMAPSIN 2 (BETA-SECRETASE, BACE) IMMUNIZATION AS SPECIFIC AND SAFE THERAPY FOR ALZHEIMER’S DISEASE