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Formulation of a Medical Food Cocktail for Alzheimer's Disease: Beneficial Effects on Cognition and Neuropathology in a Mouse Model of the Disease

Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California, United States of America.
PLoS ONE (Impact Factor: 3.53). 11/2010; 5(11):e14015. DOI: 10.1371/journal.pone.0014015
Source: PubMed

ABSTRACT Dietary supplements have been extensively studied for their beneficial effects on cognition and AD neuropathology. The current study examines the effect of a medical food cocktail consisting of the dietary supplements curcumin, piperine, epigallocatechin gallate, α-lipoic acid, N-acetylcysteine, B vitamins, vitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease.
The study found that administering the medical food cocktail for 6 months improved cortical- and hippocampal- dependent learning in the transgenic mice, rendering their performance indistinguishable from non-transgenic controls. Coinciding with this improvement in learning and memory, we found that treatment resulted in decreased soluble Aβ, including Aβ oligomers, previously found to be linked to cognitive functioning.
In conclusion, the current study demonstrates that combination diet consisting of natural dietary supplements improves cognitive functioning while decreasing AD neuropathology and may thus represent a safe, natural treatment for AD.

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Available from: Curt Hendrix, Aug 17, 2015
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    • "N-acetylcysteine (NAC) is an antioxidant and a precursor of glutathione that has been shown to rescue the brain from free radical injury after focal cerebral ischemia (Khan et al., 2004). NAC also reversed cognitive impairment and oxidative stress in aged and Tg2576 mutant mice (Farr et al., 2003; Fu et al., 2006; Parachikova et al., 2010). The antiporter system Xc − , which belongs to the family of heterodimeric amino acid transporters, imports the amino acid cystine into cells with a 1:1 countertransport of glutamate. "
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    ABSTRACT: Autism-like phenotypes in male valproate (VPA)-exposed offspring have been linked to high glutamatergic neurotransmission in the thalamic-amygdala pathway. Glial cystine/glutamate exchange (system Xc(-)), which exchanges extracellular cystine for intracellular glutamate, plays a significant role in the maintenance of extracellular glutamate. N-acetylcysteine (NAC) is a cystine prodrug that restores extracellular glutamate by stimulating system Xc(-). In this study, we examined the effects of NAC on autism-like phenotypes and neurotransmission in the thalamic-amygdala synapses, as well as the involvement of metabotropic glutamate receptors 2/3 (mGluR2/3). Valproate-treated rats received a single intraperitoneal injection of 500 mg/kg NaVPA on E12.5. On postnatal day 21 (P21), NAC or saline was administered once daily for 10 days. From day 8 to 10, NAC was given 1/2 h prior to behavioral testing. Chronic administration of NAC restored the duration and frequency of social interaction and ameliorated anxiety-like behaviors in VPA-exposed offspring. In amygdala slices, NAC treatment normalized the increased frequency of mEPSCs and decreased the paired pulse facilitation (PPF) induced by VPA exposure. The effects of NAC on social interaction and anxiety-like behavior in the VPA-exposed offspring were blocked after intra-amygdala infusion of mGluR2/3 antagonist LY341495. The expressions of mGluR2/3 protein and mGluR2 mRNA were significantly lower in the VPA-exposed offspring. In contrast, the mGluR3 mRNA level did not differ between the saline- and VPA-exposed offspring. These results provide the first evidence that the disruption of social interaction and enhanced presynaptic excitatory transmission in VPA-exposed offspring could be rescued by NAC, which depends on the activation of mGluR2/3.
    Frontiers in Behavioral Neuroscience 06/2014; 8:219. DOI:10.3389/fnbeh.2014.00219 · 4.16 Impact Factor
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    • "In addition, the supplement of compound nutrients from natural dietary supplements may have some potential value for AD treatment. Parachikova et al. (2010) have demonstrated that medical food cocktail could improve cognitive function in AD models. "
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    ABSTRACT: Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease- modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy.
    Progress in Neurobiology 07/2013; 108. DOI:10.1016/j.pneurobio.2013.06.004 · 10.30 Impact Factor
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    • "c o m / l o c a t e / n e u ro p h a r m different sources in the cell, antioxidants that stabilize mitochondrial respiratory function and decrease mitochondrial production of reactive oxygen species (ROS) have been pursued as therapies for AD treatment. This approach is supported by the findings that the antioxidant peptide SS31, mitoQ (Calkins et al., 2011; Manczak et al., 2010), alpha-lipoic acid (Quinn et al., 2007), Coenzyme Q10 (Chaturvedi and Beal, 2008), the natural polyphenols resveratrol (Kim et al., 2007), curcumin (Frautschy et al., 2001; Ishrat et al., 2009), and green tea epigallocatechin gallate (EGCG) (Rezai- Zadeh et al., 2008), as well as other combinations of antioxidants (Parachikova et al., 2010), can slow the rate of or reverse cognitive dysfunction in Alzheimer's rodent models. However, some antioxidants have been shown to decrease oxidative damage without preventing cognitive dysfunction (Siedlak et al., 2009). "
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    ABSTRACT: Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APP(sw)) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APP(sw) mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APP(sw) showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A(2a) and A(1) adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APP(sw) transgenic mouse and cell models of Alzheimer's disease.
    Neuropharmacology 09/2012; 63(8):1368-79. DOI:10.1016/j.neuropharm.2012.08.018 · 4.82 Impact Factor
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