Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome

Helm, Susan; Blayney, Morgan; Whited, Taylor; Noroozi, Mahjabin; Lin, Sen; Kern, Semira; Salehi, Ahmad

doi:10.3389/fncel.2017.00161

Cited by 5 publications

(6 citation statements)

References 55 publications

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“…Mice require less than 10 min to build a nest ( 39 ), and standard experimental protocol allows nest building for the duration of the 12 h dark period. Similar to a previous study’s findings, the folic acid deficient mice in both weeks 2 and 6.5 were significantly less capable of building a nest than the mice fed adequate folic acid and protein, p < 0.05 ( 12 ). Mice performed nest building activity during week 2 as they were acclimating to the experimental diets and at week 6.5, toward the end of the study.…”

Section: Resultssupporting

confidence: 87%

“…Despite contrary studies, there exists a narrow advantage of supplementation with folic acid for loss of learning memory in dementia ( 11 ). One study in Ts65Dn mice fed folic acid deficient diets documented shortened dendritic lengths in the dentate gyrus, cells that play a significant role in attention and contextual learning ( 12 ). In addition to protein and folate, a moderate, chronic intensity of exercise is necessary for an optimal inflammatory response as an efficient strategy for prevention of chronic disease ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota

Tuska

Helm²,

Graf³

et al. 2023

Front. Nutr.

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Intestinal microbiota, diet, and physical activity are inextricably linked to inflammation occurring in the presence of tumor progression and declining neurocognition. This study aimed to explore how fecal microbiota, inflammatory biomarkers, and neurocognitive behavior are influenced by voluntary exercise and surplus dietary protein and folic acid which are common health choices. Dietary treatments provided over 8 weeks to C57BL/CJ male mice (N = 76) were: Folic Acid (FA) Protein (P) Control (FPC, 17.9% P; 2 mgFA/kg); Folic Acid Deficient (FAD); Folic Acid Supplemented (FAS; 8 mgFA/kg); Low Protein Diet (LPD, 6% P); and High Protein Diet (HPD, 48% P). FAS mice had decreased plasma HCys (p < 0.05), therefore confirming consumption of FA. Objectives included examining influence of exercise using Voluntary Wheel Running (VWR) upon fecal microbiota, inflammatory biomarkers C - reactive protein (CRP), Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), nuclear factor kappa ß subunit (NF-κßp65), Caspase-3 (CASP3), Tumor Necrosis Factor-alpha (TNF-α), and neurocognitive behavior. CRP remained stable, while a significant exercise and dietary effect was notable with decreased VEGF (p < 0.05) and increased CASP3 (p < 0.05) for exercised HPD mice. Consumption of FAS did significantly increase (p < 0.05) muscle TNF-α and the ability to build a nest (p < 0.05) was significantly decreased for both FAD and LPD exercised mice. Rearing behavior was significantly increased (p < 0.05) in mice fed HPD. An emerging pattern with increased dietary protein intake revealed more distance explored in Open Field Testing. At week 1, both weighted and unweighted UniFrac principal coordinates analysis yielded significant clustering (permanova, p ≤ 0.05) associated with the specific diets. Consumption of a HPD diet resulted in the most distinct fecal microbiota composition. At the phylum level–comparing week 1 to week 8–we report a general increase in the Firmicutes/Bacteroidetes ratio, characterized by an outgrowth of Firmicutes by week 8 in all groups except the HPD. MaAsLin2 analysis corroborates this finding and emphasizes an apparent inversion of the microbiome composition at week 8 after HPD. Explicit modification of oncogenic inflammatory biomarkers and fecal microbiome post high FA and protein intake along with voluntary exercise contributed to current underlying evidence that this diet and exercise relationship has broader effects on human health and disease–perhaps importantly as a practical modulation of cancer progression and declining neurocognition.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota

Tuska

Helm²,

Graf³

et al. 2023

Front. Nutr.

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“…This observed folate deficiency in patients with DS is particularly intriguing when taking into account reported gene-environment risk factors in certain populations that support the notion that peri-conceptional nutritional supplementation may reduce the risk of having a child with DS in mothers carrying polymorphisms in certain folate pathway genes 30 . These findings of folate depletion in children with DS also highlight recent work describing the impact of folate depletion on brain structure and function in a mouse model of DS with the possible implication that folate insufficiency promotes the progression of structural and functional abnormalities in DS 31 . However, further research is needed to investigate the role of folate insufficiency in cognitive dysfunction in DS and the potential role for folate status monitoring and supplementation as an approach to prevent cognitive decline.…”

Section: Discussionsupporting

confidence: 70%

Untitled

2020

J Human Clin Gen

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability and recent work has demonstrated that this population has a reduction in erythrocyte (RBC) folate concentrations, which may represent a mechanistic basis for enhanced anti-folate drug toxicity observed in these patients. In this study, folate concentrations were measured in whole blood, plasma, and RBCs in an independent cohort of children with DS (n=85); and confirms previous findings that this population has lower circulating folate concentrations compared to a control cohort consisting of juvenile arthritis patients (n=99). RBC folate concentrations were 29% lower in patients with DS, and by multivariable regression analysis reduced RBC folate concentrations were associated with: DS diagnosis (p=0.0019), lack of dietary folate supplementation (p=0.006) and female gender (p=0.03). Patients with DS supplemented with dietary folate in the form of a daily multivitamin (MVI) had 25% higher RBC folate concentrations (p=0.07), and were comparable to the RBC folate concentrations in the control cohort not receiving an MVI. However, girls with DS did not exhibit the same degree of folate repletion as boys who were supplemented with MVI. These data confirm previous findings that children with DS have reduced circulating folate concentrations; however, those receiving daily MVI had RBC folate concentrations comparable to patients without DS. Female patients with DS appear to have a limited response to folate supplementation compared to males, and thus may be at increased risk for clinical features of folate deficiency and drug toxicity with anti-folate therapies.

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“…Other researchers reported that the vitamin deficiency exacerbated the cognitive impairment [ 11 , 13 ]. A recent study showed that folate deficiency impaired cognition and attention during the nesting test in Ts65Dn mice [ 14 ]. However, these studies cannot determine the role of folate in cognitive function due to other B vitamins that were also deficient in the diet.…”

Section: Introductionmentioning

confidence: 99%

Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice

Zhao

Yuan

et al. 2018

PLoS ONE

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Previous studies have shown that folate levels were decreased in patients with type 2 diabetes (T2D) and further lowered in T2D patients with cognitive impairment. However, whether folate deficiency could cause T2D and subsequent cognitive dysfunction is still unknown. The present study aimed to explore the effects of chronic folate deficiency (CFD) on glucose and lipid metabolism and cognitive function in mice. Seven-week-old mice were fed with either a CFD or control diet for 25 weeks. Serum folate was significantly reduced, whereas serum total homocysteine was significantly increased in the CFD group. Moreover, CFD induced obesity after a 6-week diet treatment, glucose intolerance and insulin resistance after a 16-week-diet treatment. In addition, CFD reduced the hepatic p-Akt/Akt ratio in response to acute insulin administration. Moreover, CFD increased serum triglyceride levels, upregulated hepatic Acc1 and Fasn mRNA expression, and downregulated hepatic Cd36 and ApoB mRNA expression. After a 24-week diet treatment, CFD induced anxiety-related activities and impairment of spatial learning and memory performance. This study demonstrates that folate deficiency could induce obesity, glucose and lipid metabolism disorders and subsequent cognitive dysfunction.

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Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome

Cited by 5 publications

References 55 publications

Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota

Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota

Untitled

Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice

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