Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age.

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). Folate-deficient diet consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions.

Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides.

Dysregulation of myelin sulfatides is a risk factor for cognitive decline with age. Vitamin K is present in high concentrations in the brain and has been implicated in the regulation of sulfatide metabolism. Our objective was to investigate the age-related interrelation between dietary vitamin K and sulfatides in myelin fractions isolated from the brain regions of Fischer 344 male rats fed one of two dietary forms of vitamin K: phylloquinone or its hydrogenated form, 2',3'-dihydrophylloquinone (dK), for 28 days. Both dietary forms of vitamin K were converted to menaquinone-4 (MK-4) in the brain. The efficiency of dietary dK conversion to MK-4 compared to dietary phylloquinone was lower in the striatum and cortex, and was similar to that in the hippocampus. There were significant positive correlations between sulfatides and MK-4 in the hippocampus (phylloquinone-supplemented diet, 12 and 24 months; dK-supplemented diet, 12 months) and cortex (phylloquinone-supplemented diet, 12 and 24 months). No significant correlations were observed in the striatum. Furthermore, sulfatides in the hippocampus were significantly positively correlated with MK-4 in serum. This is the first attempt to establish and characterize a novel animal model that exploits the inability of dietary dK to convert to brain MK-4 to study the dietary effects of vitamin K on brain sulfatide in brain regions controlling motor and cognitive functions. Our findings suggest that this animal model may be useful for investigation of the effect of the dietary vitamin K on sulfatide metabolism, myelin structure and behavior functions.

Depression and plasma amyloid beta peptides in the elderly with and without the apolipoprotein E4 allele.

Depression associated with low plasma amyloid-beta peptide 42 (Abeta42) leading to a high ratio of Abeta40/Abeta42, a biomarker of Alzheimer disease (AD), may represent a unique depression subtype. The relationship between low plasma Abeta42 in depression and the major risk factor of AD, apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Abeta40 and Abeta42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Abeta42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/mL, P=0.006], a higher Abeta40/Abeta42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P=0.03], and lower cognitive function (mean+/-SD of Mini-Mental State Examination: 24.5+/-3.1 vs. 25.5+/-3.3, P<0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Abeta42 and a higher Abeta40/Abeta42 ratio than non-ApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Abeta42 and ApoE4 (odds ratio=3.94, 95% confidence interval=1.50, 10.33, P=0.005), denoting low plasma Abeta42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Abeta42 and a higher Abeta40/Abeta42 ratio in plasma compared with non-ApoE4 carriers without depression in the homebound elderly. As a combination of low plasma Abeta42 and high plasma Abeta40 has been shown to increase the risk of AD in 2 large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine.

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

Aging modifies brain region-specific vulnerability to experimental oxidative stress induced by low dose hydrogen peroxide.

Our previous studies demonstrated a significant decline in brain function and behavior in Fischer 344 (F344) rats with age. The present study was designed to test the hypothesis that dysregulation in calcium homeostasis (as assessed through (45)Ca flux) may contribute to the increase in age-related vulnerability to oxidative stress in brain regions, and result in a deficit in behavior-mediated signaling. Crude membrane (P-2) and more purified synaptosomal fractions were isolated from the striatum, hippocampus, and frontal cortex of young (6 months) and old (22 months) F344 rats and were assessed for calcium flux and extracellular-regulated kinase activity 1 (ERK) under control and oxidative stress conditions induced by low dose hydrogen peroxide (final concentration 5 microM). The level of oxidative stress responses was monitored by measuring reactive oxygen species (ROS) and glutathione (GSH). The results showed a significant difference in oxidative stress responses between young and old rats in evaluated brain regions. Old rats showed higher sensitivity to oxidative stress than young rats. The present findings show the differential effects of oxidative stress on calcium flux in brain regions with age that are dependent upon the brain areas examined and the fraction assessed. The accumulation of ROS and the decrease in GSH in the frontal cortex were sufficient to decrease ERK activity in old rats. This is the first study, to our knowledge, that demonstrates age-related differential sensitivity to oxidative stress expressed as a function of behavior-mediated signaling and stress levels among different fractions isolated from brain regions controlling behavior.

Age-related changes in neutral sphingomyelin-specific phospholipase C activity in striatum, hippocampus, and frontal cortex: implication for sensitivity to stress and inflammation.

UNLABELLED: Previous studies show the enrichment of mammalian brain with neutral sphingomyelin-specific phospholipase C (ceramide-phosphocholine phosphodiesterase, EC 3.1.4.12; N-Sase), a key enzyme of sphingolipid metabolism and sphingolipid-induced signaling. OBJECTIVE: The objective of this study was to evaluate the membrane-associated and cytosolic N-Sase activities in the brain regions associated with behavior (striatum, hippocampus, and frontal cortex). RESULTS: Results showed higher membrane-associated N-Sase activity as compared to the N-Sase activity in the cytosolic fractions of all the evaluated brain regions. In the hippocampus, the N-Sase activity was significantly higher than in the striatum and cortex. In addition, age-related changes in the hippocampal N-Sase activities were profoundly higher than in the respective fractions isolated from the striatum and cortex. Age-related decreases in the hippocampal and striatal cytosolic N-Sase activities were accompanied by increases in the membrane N-Sase activities in those brain regions. There was a significant increase in the cortical membrane-associated N-Sase activity with age; however, to a much lesser extend than in other brain regions. The increase in the hippocampal membrane-associated N-Sase activity was accompanied by a higher expression of the inflammatory marker, interleukin-1 beta (IL-1 beta), with age. One of the important findings of the present study is the region-specific expression of heat shock protein 70 (hsp70). Frontal cortex showed lower hsp70 expression in both young and old age groups as compared to the striatal and hippocampal hsp70 levels which can contribute to the recently reported higher cortical sensitivity to oxidative stress. CONCLUSION: In conclusion (a) our results, for the first time to our knowledge, demonstrated the association between the N-Sase activity and the stress/inflammatory markers expression in the brain regions controlling behavior; (b) these findings suggest the role of N-Sase as a contributor to the increased stress and inflammatory sensitivity among the brain regions with age.