Obesity Leads to Tissue, but not Serum Vitamin A Deficiency : Scientific Reports

 "Obesity negatively affects multiple metabolic pathways, but little is known about the impact of obesity on vitamin A (VA)[retinol (ROL)], a nutrient that regulates expression of genes in numerous pathways essential for human development and health. We demonstrate that obese mice, generated from a high fat diet (HFD) or by genetic mutations (i.e., ob/ob; db/db), have greatly reduced ROL levels in multiple organs, including liver, lungs, pancreas, and kidneys, even though their diets have adequate VA. However, obese mice exhibit elevated serum VA. Organs from obese mice show impaired VA transcriptional signaling, including reductions in retinoic acid receptor (RARα, RARβ2 and RARγ) mRNAs and lower intracellular ROL binding protein Crbp1 (RBP1) levels in VA-storing stellate cells. Reductions in organ VA signaling in obese mice correlate with increasing adiposity and fatty liver (steatosis), while with weight loss VA levels and signaling normalize. Consistent with our findings in obese mice, we show that increasing severity of fatty liver disease in humans correlates with reductions in hepatic VA, VA transcriptional signaling, and Crbp1 levels in VA storing stellate cells. Thus, obesity causes a “silent” VA deficiency marked by reductions in VA levels and signaling in multiple organs, but not detected by serum VA."



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Retinoic acid-elicited RARα/RXRα signaling attenuates Aβ production by directly inhibiting γ-secretase-mediated cleavage of amyloid precursor protein.

Retinoic acid (RA)-elicited signaling has been shown to play critical roles in development, organogenesis, and the immune response. RA regulates expression of Alzheimer's disease (AD)-related genes, and attenuates amyloid pathology in a transgenic mouse model. In this study, we investigated whether RA can suppress the production of amyloid- (A) through direct inhibition of γ-secretase activity. We report that RA treatment of cells results in significant inhibition of -secretase-mediated processing of the amyloid precursor protein C-terminal fragment APP-C99, as compared to DMSO-treated controls. RA-elicited signaling was found to significantly increase accumulation of APP-C99, and decrease production of secreted Aβ40. In addition, RA-induced inhibition of -secretase activity was found to be mediated through significant activation of extracellular signal-regulated kinases (ERK1/2). Treatment of cells with the specific ERK inhibitor PD98059 completely abolished RA-mediated inhibition of γ-secretase. Consistent with these findings, RA was observed to inhibit secretase-mediated proteolysis of full-length APP. Finally, we have established that RA inhibits γ-secretase through nuclear retinoic acid receptor-alpha (RARα) and retinoid X receptor-alpha (RXRα). Our findings provide a new mechanistic explanation for the neuroprotective role of RA in AD pathology, and add to the previous data showing the importance of RA signaling as a target for AD therapy.

All-trans retinoic acid rescues memory deficits and neuropathological changes in mouse model of streptozotocin-induced dementia of Alzheimer's type.

Recent studies have revealed that aberrant vitamin A signaling may lead to memory deficits in rodents. Present study investigates the potential of all-trans-retinoic acid (ATRA) an agonist at retinoid acid family of receptors, in cognitive dysfunctions associated with experimental dementia. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v)] was administered on alternate days (day 1 and day 3) to induce dementia in Swiss albino mice. STZ mice were administered ATRA (10 mg/kg; 20 mg/kg, p.o.) for a total of 19 days following second i.c.v injection of STZ [day 4 to day 22]. Morris water maze (MWM) test was performed on days 19, 20, 21, 22 and 23 to assess learning and memory of the animals. Following MWM test, the animals were sacrificed for biochemical and histopathological studies. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice showed marked accentuation of AChE activity, TBARS and MPO levels along with fall in GSH level. Further the stained micrographs of STZ-treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. ATRA treatment significantly attenuated STZ-induced memory deficits, biochemical and histopathological alterations. The findings demonstrate that the memory restorative ability of ATRA may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.

Tamibarotene: a candidate retinoid drug for Alzheimer's disease.

Tamibarotene (Am80), a synthetic retinoid approved in Japan for treatment of acute promyelocytic leukemia (APL), is a retinoic acid receptor (RAR) agonist with high specificity for RARα and RARβ over RARγ. Temporarily and spatially specific expression of RARs suggests their pivotal roles in the adult brain. Am80 is considered to be a promising candidate drug for treatment of Alzheimer's disease (AD) because of its transcriptional controls of multiple target genes involved in etiology and pathology of AD. In APP23 AD model mice, administration of Am80 decreased the deposition of insoluble amyloid-β(42). In senescence-accelerated mice (SAMP8), Am80 ameliorated the decrease of cortical acetylcholine, as well as reducing anxiety in behavioral tests and improving the sleep deficit. Am80 also effected a significant improvement of memory in the rat scopolamine-induced memory deficit model. Like other retinoids, Am80 also has an immunomodulatory effect and reduces secretion of proinflammatory cytokines and chemokines by astrocytes and microglia surrounding amyloid-β plaques. In a rat experimental autoimmune encephalomyelitis model, Am80 reduced inflammatory cytokines and showed significant efficacy. Retinoids also promote differentiation of neural stem cells, and Am80 improved the recovery of spinal cord-injured rats. Am80 may also improve vascular factors involved in onset and/or progression of AD. Am80 has been in clinical use for treatment of APL in Japan since 2005, and has been reported to have fewer side effects than other retinoids. We have recently started a clinical study to evaluate the efficacy and safety of Am80 for the treatment of Alzheimer's disease.

Vitamin C and beta-carotene might protect against dementia

Forgetfulness, lack of orientation, cognitive decline… about 700, 000 Germans suffer from Alzheimer's disease (AD). Now researchers from the University of Ulm, among them the Epidemiologist Professor Gabriele Nagel and the Neurologist Professor Christine von Arnim, have discovered that the serum-concentration of the antioxidants vitamin C and beta-carotene are significantly lower in patients with mild dementia than in control persons. It might thus be possible to influence the pathogenesis of AD by a person's diet or dietary antioxidants. 74 AD-patients and 158 healthy controls were examined for the study that has been published in the "Journal of Alzheimer's Disease" (JAD).

Read more at: http://medicalxpress.com/news/2012-09-vitamin-beta-carotene-dementia.html#jCp

Vitamin and mineral intakes in adults with mood disorders

OBJECTIVE: The purpose of this study was to investigate the nutrient intakes of people with mood disorders. Method: A cross-sectional survey using 3-day food records was carried out in 97 adults with bipolar or major depressive disorder to compare nutrient intakes with Dietary Reference Intakes and British Columbia Nutrition Survey (BCNS) data. Blood levels of selected nutrients were compared to reference ranges. Bivariate and multivariate analyses examined the effects of sociodemographic and clinical variables on nutrient intakes. Results: The average age of respondents was 46 (±13) years; most were women (n = 69) who had less than a university degree (n = 60) and whose incomes were in the government-defined lower range (n = 39). Compared with the BCNS, a larger proportion of the sample was below the estimated average requirement for thiamin (26% vs 8%), riboflavin (21% vs 4%), folate (64% vs 27%), phosphorous (12% vs 1%), and zinc (39% vs 15%; all P < 0.0001), as well as vitamin B(6) (25% vs 16%) and vitamin B(12) (27% vs 8%; both P < 0.05). Combined intakes of food and supplements helped reduce the prevalence of inadequacy; however, with supplementation, the proportion of participants exceeding the tolerable upper intake levels for niacin, vitamin B(6), folate, vitamin C, calcium, magnesium, iron, and zinc ranged from 1%-8%. Income, relationship status, age, gender, and caloric intake were associated with intakes of many nutrients. Types of medications were associated with nutrient intakes, as lower intakes of thiamin and phosphorous (P < 0.05) were found with antidepressant use, higher calcium and iron intakes (P < 0.05) were associated with antianxiety medication use, and magnesium intakes were increased with mood stabilizers (regression coefficient = 52.61, P < 0.05, 95% confidence interval = 0.74 to 104.48). Conclusions: Adults with mood disorders are at risk for many nutrient inadequacies, as well as occasional excesses; social, demographic, and clinical factors may affect their nutrient intakes.

Can vitamin B pills prevent Alzheimer's? - Health News - NHS Choices

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Alzheimer's genes risk factors and pathways :

Vitamin A supplements for children could save 600,000 lives a year, experts predict

Vitamin A deficiency has also been implicated in diseases related to old age -for example Alzheimer's disease Jimenez et al, 1999 where many susceptibility genes, including APOE4 appear to be involved in vitamin A function ISRN Neurology, 2011

Alzheimer's disease genes risk factors and pathways :

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