Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1-42 mediated cytotoxicity

Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4,5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1-42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4,5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the co-localisation between the chaperone and Aβ1-42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1-42 cytotoxicity in our cell model

Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid

Background: Inflammation is associated with A beta pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1 beta and TNF-alpha which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces A beta pathology and is neuroprotective. Low concentrations of IFN-gamma modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17-19 months) Tg2576 mice to a response that reduces A beta pathology. Methods: TG (n = 29) and WT (n = 27) mice were divided into sedentary (SED) and exercised (RUN) groups. RUN animals were provided an in-cage running wheel for 3 weeks. Tissue was harvested and hippocampus and cortex dissected out. Quantitative data was analyzed using 2 x 2 ANOVA and student's t-tests. Results: IL-1 beta and TNF-alpha were significantly greater in hippocampi from sedentary Tg2576 (TG(SED)) mice than in wildtype (WT(SED)) (p = 0.04, p = 0.006). Immune response proteins IFN-gamma and MIP-1 alpha are lower in TG(SED) mice than in WT(SED) (p = 0.03, p = 0.07). Following three weeks of voluntary wheel running, IL-1 beta and TNF-alpha decreased to levels indistinguishable from WT. Concurrently, IFN-gamma. and MIP-1 alpha increased in TG(RUN). Increased CD40 and MHCII, markers of antigen presentation, were observed in TG(RUN) animals compared to TG(SED), as well as CD11c staining in and around plaques and vasculature. Additional vascular reactivity observed in TG(RUN) is consistent with an alternative activation immune pathway, involving perivascular macrophages. Significant decreases in soluble A beta(40) (p = 0.01) and soluble fibrillar A beta (p = 0.01) were observed in the exercised transgenic animals. Conclusion: Exercise shifts the immune response from innate to an adaptive or alternative response. This shift in immune response coincides with a decrease in A beta in advanced pathological states

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 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

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

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