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: 3.23). 11/2010; 5(11):e14015. DOI: 10.1371/journal.pone.0014015
Source: PubMed


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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    • "The CDS (Table 1) was designed to target five major mechanisms associated with aging: inflammation, oxidative stress, mitochondrial dysfunction, insulin resistance and membrane integrity. Although this approach may not identify contributions of any one ingredient, mounting evidence supports the potent neuroprotective effects of CDSs exhibiting some overlap in ingredients or physiological targets (Milgram et al., 2002; Parachikova et al., 2010). Broad-spectrum, antioxidant-rich micronutrient supplementation also shows promise in treatment of mood disorders, while single nutrient supplements generally produce weak results (Rucklidge and Kaplan, 2013; Popper, 2014). "
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    ABSTRACT: Chronic stress has a profoundly negative impact on the brain (1). Even acute stress exposure can markedly decrease neurogenesis (2), with significant implications for plasticity, memory, and mood (3). It is evident that the heightened plasticity of these newborn neurons makes them responsive to many environmental factors, which consequently affect behaviour. Some factors that robustly enhance neurogenesis and can mitigate the effects of stress and depression include antidepressant medications (4), dietary antioxidants (5) and exercise (6). At the physiological level, these factors are associated with biochemical processes and signaling pathways which are also altered in age-related cognitive decline, such as neurotrophin expression (7), cellular oxidative stress (5), inflammation (8) and mTOR regulation (9). A complex dietary supplement designed to counteract five potential mechanisms of ageing: inflammation, oxidative stress, mitochondrial dysfunction, insulin resistance and membrane integrity, has been shown to ameliorate physiological and cognitive decline in aged transgenic growth hormone mice (an accelerated aging model) and aged wild type control mice (10). We therefore predicted that this supplement combined with aerobic exercise would exert potent neuroprotective effects against chronic unpredictable stress in young adult mice. Four weeks of unpredictable mild stress strongly affected all stressed groups, as indicated by reduced saccharin preference and increased adrenal weights. Interestingly, the combination of dietary supplementation and aerobic exercise buffered the adverse effects of stress, as reflected in the number of doublecortin-positive immature neurons in the dentate gyrus, the sectional area of the dentate gyrus and CA1, and serum vascular endothelial growth factor levels. In contrast, these benefits were not observed in chronically stressed animals exposed to dietary supplementation or exercise alone. It is expected that RT-PCR analysis of hippocampal brain-derived neurotrophic factor mRNA, currently under investigation using samples from these animals, will reveal a similar pattern. Given the well-established effects of aerobic exercise (6) on neurogenesis in non-stressed animals, it is interesting that in stressed animals we observed no such benefit of either exercise or dietary supplementation alone, whereas the combination of diet supplementation and exercise exerted potent neuroprotective effects on hippocampal integrity. Our findings have important clinical implications for those suffering chronic stress-related psychiatric disorders such as major depression. (1) Gould, E.; McEwen, B. S.; Tanapat, P.; Galea, L. A.; Fuchs, E. J. Neurosci. 1997, 17, 2492–2498. (2) Gould, E.; Cameron, H. A.; Daniels, D. C.; Woolley, C. S.; McEwen, B. S. J. Neurosci. 1992, 12, 3642–3650. (3) Willner, P.; Towell, A.; Sampson, D.; Sophokleous, S.; Muscat, R. Psychopharmacology (Berl). 1987, 93, 358–364. (4) Malberg, J. E.; Eisch, A J.; Nestler, E. J.; Duman, R. S. J. Neurosci. 2000, 20, 9104–9110. (5) Valente, T.; Hidalgo, J.; Bolea, I.; Ramirez, B.; Anglés, N.; Reguant, J.; Morelló, J. R.; Gutiérrez, C.; Boada, M.; Unzeta, M. J. Alzheimers. Dis. 2009, 18, 849–865. (6) van Praag, H.; Kempermann, G.; Gage, F. H. Nat. Neurosci. 1999, 2, 266–270. (7) Sairanen, M.; Lucas, G.; Ernfors, P.; Castrén, M.; Castrén, E. J. Neurosci. 2005, 25, 1089–1094. (8) Goshen, I.; Kreisel, T.; Ben-Menachem-Zidon, O.; Licht, T.; Weidenfeld, J.; Ben-Hur, T.; Yirmiya, R. Mol. Psychiatry 2008, 13, 717–728. (9) Ota, K. T.; Liu, R.; Voleti, B.; Maldonado-Aviles, J. G.; Duric, V.; Iwata, M.; Dutheil, S.; Duman, C.; Boikess, S.; Lewis, D. A.; Stockmeier, C. A.; DiLeone, R. J.; Rex, C.; Aghajanian, G. K.; Duman, R. S. Nat. Med. 2014, 20, 531–535. (10) Aksenov, V.; Long, J.; Liu, J.; Szechtman, H.; Khanna, P.; Matravadia, S.; Rollo, C. D. Age (Dordr). 2013, 35, 23–33.
    Adult Neurogenesis: Evolution, Regulation and Function, Center for Regenerative Therapies, Dresden, Germany; 05/2015
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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 · 3.27 Impact Factor
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    • "While NAC has not been subject to studies within cancer patients with cognitive dysfunction, it has been trialled in dementia patients (specifically in those with Alzheimer’s Disease) and in patients with bipolar mood disorder [51,52]. In a randomised, double-blind trial of NAC against placebo in 43 patients who met the diagnostic criteria for probable Alzheimer’s Disease, Adair et al. gave NAC at a dose of 50 mg/kg/d and measured outcomes using the MMSE at baseline, 12 weeks and 24 weeks. "
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    ABSTRACT: Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction.
    BMC Neurology 10/2013; 13(1):153. DOI:10.1186/1471-2377-13-153 · 2.04 Impact Factor
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