levoleucovorin and Alzheimer-Disease

Patients with Alzheimer's disease have increased risk of developing heart disease, which therefore highlights the need for strategies aiming at reducing Alzheimer's disease-related cardiovascular disease. Folic acid and folinic acid are beneficial to the heart. We aimed to investigate the benefits of folic acid and folinic acid in heart of patients with late-stage Alzheimer's disease. Twelve 16-month-old mice of triple-transgenic late-stage Alzheimer's disease were divided into three groups: Alzheimer's disease group, Alzheimer's disease + folic acid group, and Alzheimer's disease + folinic acid group. The mice were administered 12 mg/kg folic acid or folinic acid once daily via oral gavage for 3 months. In the folic acid and folinic acid treatment groups, the intercellular space was reduced, compared with the Alzheimer's disease group. TUNEL assay and western blot images showed that the number of apoptotic cells and the apoptosis-related protein expression were higher in the Alzheimer's disease group than in other two treated groups. Folic acid and folinic acid induced the IGF1R/PI3K/AKT and SIRT1/ AMPK pathways in the hearts of mice with Alzheimer's disease. Our results showed that folic acid and folinic acid treatment increased survival and SIRT1 expression to reduce apoptotic proteins in the heart. The aging mice treated with folinic acid had more IGF1R and SIRT1/AMPK axes to limit myocardial cell apoptosis. In conclusion, folic acid and folinic acid promote cardiac cell survival and prevent apoptosis to inhibit heart damage in aging mice with triple-transgenic late-stage Alzheimer's disease. In particular, folinic acid provides a better curative effect than folic acid.

Topics: Aging; Alzheimer Disease; AMP-Activated Protein Kinases; Animals; Folic Acid; Humans; Leucovorin; Mice; Mice, Transgenic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Sirtuin 1

Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.

Topics: Aged; Alzheimer Disease; Animals; Cardiomegaly; Disease Models, Animal; Fibrosis; Folic Acid; Humans; Leucovorin; Mice; Mice, Transgenic

Previously in the search for chemopreventatives for Alzheimer's disease (AD), microbial cells with amyloid-beta (Abeta) protein fusions have been used to screen for compounds that reduce the aggregation, misfolding or oligomerization of Abeta. In the current study, such a system has been used to look at the effect of folate, whose deficiency has been associated with AD. A folate-deficient yeast strain producing Abeta fused to green fluorescent protein (GFP) that spontaneously misfolds/aggregates and suppresses green fluorescence was used to examine the effects of folinic acid on Abeta-GFP fluorescence. At levels that did not affect growth or plasmid stability, increasing levels of folinic acid led to increasing green fluorescence, suggesting folate can assist with preventing Abeta-misfolding/aggregation. This result supports a protective role for folate and suggests that yeast assays may provide significant new approaches for testing of AD chemopreventatives.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biological Assay; Flow Cytometry; Folic Acid; Gene Deletion; Green Fluorescent Proteins; Leucovorin; Peptide Synthases; Plasmids; Protein Folding; Saccharomyces cerevisiae; Vitamin B Complex