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

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

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

BackgroundDietary 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 vitaminsvitamin C, and folate on cognitive functioning and the AD hallmark features and amyloid-beta (Aβ) in the Tg2576 mouse model of the disease.Principal FindingsThe 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.ConclusionIn 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

Prevention of hippocampal spatial memory deficits with medical food cocktail diet in Tg2576 mice.

<p>Medical food cocktail was given to Tg2576 and non-transgenic control (nonTg) mice at 6 months of age, at a low and high (3x higher) dose. After 5 months of treatment, mice were tested for cognitive functioning on hippocampal and cortical dependent tasks. Mice were trained and tested on the spatial memory version of the Morris water maze (MWM; n = 10 per group). A) Acquisition curves shown for the 7 days of training on the MWM. Non-transgenic mice perform better as compared to Tg2576 starting day 2 of training (Genotype main effect day 2 F(1,45) 3.586, p = 0.0599, day 3 F(1, 45) 4.611 p = 0.0332, day 4 F(1, 45) 4.832, p = 0.0519, day 5 F(1, 45) 13.812, p = 0.003, day 6 F(1, 45) 4.021, p = 0.0465 and day 7 F(1, 45) 15.821, p = 0.0001). NonTg mice on the control diet perform significantly better on day 7 as compared to day 1 of training (p<0.0001). Tg2576 mice on the control diet also exhibited learning during the acquisition phase of the test (day 1 compared to day 7 p<0.05) but were unable to reach the 25 sec criterion after 7 days of training. Medical food cocktail improved the spatial learning of Tg2576 during training (low diet day 5 p<0.05, day 6 p<0.01, day 7 p = 0.1034; high diet day 5 p<0.01, day 6 p<0.001, day 7 p<0.01) with mice reaching criterion by day 7 of training. B) All mice started at the same level as shown by the average of trials 1 and 2 on the 1^st day of training (Genotype main effect F(1, 104) 0.094, p = 0.9107, treatment main effect F(2, 104) 0.233, p = 0.7928). C–F) Mice were given a memory probe with the platform removed at 1.5-h or 24-h following the last training trial. C) Tg2576 mice took significantly longer to reach the platform location as compared to non-transgenic mice on the control diet (p<0.05 for both 1.5 and 24-hour probe trials). Tg2576 mice treated with medical food cocktail exhibited significantly decreased latencies to cross the platform location compared to vehicle-treated mice (p<0.05 for both 1.5 and 24-hour probe trials for both low and high diet treatments). D) The deficits in memory were also evident in the number of crosses of Tg2576 as compared to the control diet treated non-transgenic mice (p<0. 05 at both 1.5 and 24 hours). Tg2576 mice treated with medical food cocktail made significantly more platform crosses at both short- and long-term probes than vehicle-treated mice (low diet (p<0.05 at both 1.5 and 24 hours; high diet p<0.01 at 1.5 and p<0.05 at 24 hours). E) Control diet treated Tg2576 mice also spent less time in the target quadrant (p<0.05 for both 1.5 and 24-hour probe trials). Tg2576 mice treated with medical food cocktail spent significantly more time in the target quadrant than vehicle-treated transgenic mice (low diet (p<0.05 at 1.5 hours; high diet p<0.05 at both 1.5 and 24 hours). F) In support of the target quadrant data, time spent in the opposite quadrant was significantly more for Tg2576 as compared to non-transgenic mice on the control diet (p<0.01 for both 1.5 and 24-hour probe trials). Tg2576 mice treated with medical food cocktail spent significantly less time in the opposite quadrant than vehicle-treated mice (low diet (p<0.01 at 1.5 and p<0.05 at 24 hours; high diet p<0.01 at both 1.5 and 24 hours). Error bars indicate SEM. * indicates significance for control Tg2576 mice vs. medical food cocktail treated Tg2576 mice.</p

Prevention of cortical memory deficits with medical food cocktail diet in Tg2576 mice.

<p>We evaluated treated and untreated Tg2576 and nonTg mice in performance of the primarily perirhinal cortex-dependent contextual task, novel object recognition. Tg2576 mice treated with medical food cocktail had significantly improved recognition indexes at both the 1.5- and 24-h probe trials, compared to vehicle Tg2576 mice (1.5 hour probe trial (low diet p<0.05, high diet p<0.01; 24 hour probe trial (p<0.01 for both low and high combination diets). Notably, nonTg mice treated with medical food cocktail showed improved recognition indexes at the 24-h probe compared to vehicle nonTg mice (p<0.05 for both low and high combination diets). Error bars indicate SEM. * indicates significance for control Tg2576 mice vs. medical food cocktail treated Tg2576 mice, ** indicates significance for control nonTg mice vs. medical food cocktail nonTg mice.</p

Components of high and low nutrient combination diets added to AIN-17 rodent chow.

<p>Components of high and low nutrient combination diets added to AIN-17 rodent chow.</p

Medical food cocktail diet reduces Aβ levels and decreases aggregation.

<p>Soluble (A) and insoluble (B) Aβ₄₀ and Aβ₄₂ levels were measured from Tg2576 whole brain homogenates from animals treated for 6 months with medical food cocktail or vehicle. A) Soluble Aβ levels were significantly reduced with medical food cocktail diet in Tg2576 mice. B) Insoluble Aβ40 levels were also significantly reduced with medical food cocktail diet in Tg2576 mice. C) Western blot analyses of protein extracts from whole-brain homogenates of Tg2576 mice treated for 6 months with either high dose medical food cocktail or vehicle shown as alternating lanes. Steady state levels of APP were unaffected by treatment, but APP CTF's C83 and C99 were reduced by medical food cocktail treatment. D) Quantification of (C) normalized to β-actin levels as a loading control. E) Dot blot analyses of brain homogenates from Tg2576 mice treated for 6 months with either high dose medical food cocktail or vehicle for Aβ oligomers or Aβ fibrils, using conformation specific antibodies, or western blot analyses for Aβ*56 using 6E10, shown as alternating lanes. Reductions in both Aβ oligomers and Aβ*56 were seen with treatment. F) Quantification of (E). Error bars indicate SEM. * indicates significance (p<0.05) for control Tg2576 mice vs. high dose medical food cocktail treated Tg2576 mice. To assess levels of low molecular weight oligomeric and soluble fibril Aβ species we used the conformation specific antibodies A11 and OC respectively. Dot blot analysis showed a 20% reduction of soluble oligomers in the brains of Tg2576 animals treated with the high combination diet (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0014015#pone-0014015-g002" target="_blank">Figure 2E, F</a>), but no differences in soluble fibrils.</p

Multivalent epigenetic marks confer microenvironment-responsive epigenetic plasticity to ovarian cancer cells

“Epigenetic plasticity” refers to the capability of mammalian cells to alter their differentiation status via chromatin remodeling-associated alterations in gene expression. While epigenetic plasticity has been best associated with lineage commitment of embryonic stem cells, recent studies have demonstrated chromatin remodeling even in terminally differentiated normal cells and advanced-stage melanoma and breast cancer cells, in context-dependent responses to alterations in their microenvironment. In the current study, we extend this attribute of epigenetic plasticity to aggressive ovarian cancer cells, by using an integrative approach to associate cellular phenotypes with chromatin modifications (“ChIP-chip”) and mRNA and microRNA expression. While we identified numerous gene promoters possessing the well-known “bivalent mark” of H3K27me3/H3K4me2, we also report 14 distinct, lesser known bi-, tri- and tetravalent combinations of activating and repressive chromatin modifications, in platinum-resistant CP 70 ovarian cancer cells. The vast majority (>90%) of all the histone marks studied localized to regions within 2,000 bp of transcription start sites, supporting a role in gene regulation. Upon a simple alteration in the microenvironment, transition from two- to three-dimensional culture, an increase (17–38%) in repressive-only marked promoters was observed, concomitant with a decrease (31–21%) in multivalent (i.e., juxtaposed permissive and repressive histone marked) promoters. Like embryonic/tissue stem and other (non-ovarian) carcinoma cells, ovarian cancer cell epigenetic plasticity reflects an inherent transcriptional flexibility for context-responsive alterations in phenotype. It is possible that this plasticity could be therapeutically exploited for the management of this lethal gynecologic malignancy

Legislative Council Reforms for 2012 and 2016

The Legal & Academic Perspective (Speaker