Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease
Introduction
Mitochondrial dysfunction and oxidative stress have been implicated in multiple neurodegenerative diseases including Alzheimer's disease (AD) (Balaban et al., 2005, Beal, 2005, Gibson et al., 2005), and the changes can be plausibly linked to plaque and tangle formation. Studies on postmortem tissues from AD patients reveal reductions in key thiamine-dependent enzymes of the pentose shunt (transketolase), the tricarboxylic acid cycle (TCA) (i.e., the α-ketoglutarate dehydrogenase complex; KGDHC) and the link of glycolysis and the TCA cycle (i.e., the pyruvate dehydrogenase complex; PDHC) in AD (Bubber et al., 2005, Gibson et al., 2000). Brains from AD patients also contain elevated levels of lipid peroxidation products, as well as protein and DNA oxidation (Nourooz-Zadeh et al., 1999, Pratico et al., 2000, Ramassamy et al., 2000, Smith et al., 1996). In a mouse model of plaque formation, partial knockout of manganese superoxide dismutase (MnSOD) elevates protein carbonyl levels, Aβ levels and increased plaque burden (Li et al., 2004). On the other hand, reducing iNOS diminishes the levels of protein tyrosine nitration products, lowers concentration of Aβ and diminishes amyloid plaque burden (Nathan et al., 2005). Furthermore, Aβ by itself is capable of producing free radicals and ROS (Butterfield et al., 1994, Hensley et al., 1994, Huang et al., 1999). Plausible mechanisms link elevated ROS to the AD-related changes in amyloid, tau and energy metabolism (Mark et al., 1997, Pappolla et al., 1998, Pratico, 2002, Smith et al., 1991).
The extensive data that supports an important role of oxidative stress in neurodegenerative disorders concomitantly support the beneficial effect of antioxidants as adjunctive or supportive therapy. Resveratrol (trans-3,5,4-trihydroxystilbene), possesses a wide range of biological effects that include anti-oxidative, anti-inflammatory and anti-carcinogenic properties. Numerous reports suggest that resveratrol acts as a potent antioxidant and induces endogenous antioxidants levels (Miller and Rice-Evans, 1995, Robb et al., 2008, Li et al., 2006). In vitro studies suggest that resveratrol may protect against β-amyloid induced oxidative cell damage in PC12 cell lines (Conte et al., 2003, Jang and Surh, 2003, Kim et al., 2007a, Kim et al., 2007b), and may promote Aβ clearance through promotion of intracellular proteosomal activity in cell lines expressing wild type or Swedish APP695 mutations (Marambaud et al., 2005).
Several clinical studies indicate that antioxidants may delay onset of neurodegenerative diseases (Engelhart et al., 2002, Morris et al., 2002). A double-blind, placebo-controlled, randomized, multicenter trial in AD patients with moderate severity demonstrated that α-tocopherol treatment slowed the progression of the disease (Sano et al., 1997). However, the effects were modest. Recent studies show that resveratrol increases longevity and delays the onset of aging in a manner similar to that of caloric restriction (Baur et al., 2006). In a model of AD and tauopathies, introduction of resveratrol directly into the brain ventricles reduces neurodegeneration in the hippocampus, prevents learning impairment, and decreases the acetylation of the known SIRT1 substrates PGC-1 α and p53 (Kim et al., 2007a). The present studies tested whether administration of resveratrol to Tg19959 mice alters plaque pathology.
Section snippets
Animals
Tg19959 mice were produced by pronuclear microinjection of (FVB·129S6F1) embryos with a cosmid insert containing APP695 with two familial AD mutations (KM670/671NL and V717F) under the control of the hamster PrP promoter (Chishti et al., 2001). Male Tg19959 mice were backcrossed to (C57/B6SJL) F1 female breeders. Genotypes of the offspring were determined by PCR analysis of tail DNA. Animals were housed at constant temperature (22 ± 2 °C), humidity (50 ± 5%) and illumination (12 h light/dark cycles)
Resveratrol was stable in the diet and not detectable in brain
A method to extract resveratrol from diet or brain was developed. Linearity, characteristics plot, standard curve, and lower limits of detection were analyzed. The retention time of resveratrol was 5.3 min (Fig. 1A). At this time, the resveratrol standard curve was linear over a wide range (Fig. 1D). The method is very sensitive. The lowest point on the standard curves was 0.5 pmole/ml. Fig. 1B represents no detectable levels of resveratrol in the control diet and Fig. 1C demonstrates the level
Discussion
Accumulating evidences from experimental and human studies suggest that oxidative stress and mitochondrial dysfunction are important causative factors in the development and progression of several neurodegenerative diseases including AD (Gibson et al., 2000, Ojaimi et al., 1999, Balaban et al., 2005). Induction of mild impairment of oxidative metabolism, oxidative stress and inflammation induced by thiamine deficiency alters BACE1 levels and metabolism of APP and/or Aβ and promotes accumulation
Acknowledgements
These studies were supported by Alzheimer's Drug Discovery Foundation & Institute for the Study of Aging and NIH grants AG14600 and P01 AG14930.
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