Microglia contribute to cognitive decline in hypercholesterolemic LDLr-/- mice.

Familial hypercholesterolemia (FH) is caused by mutations in the gene that encodes the low-density lipoprotein (LDL) receptor, which leads to an excessive increase in plasma LDL cholesterol levels. Previous studies have shown that FH is associated with gliosis, blood-brain barrier dysfunction, and memory impairment, but the mechanisms associated with these events are still not fully understood. Therefore, we aimed to investigate the role of microgliosis in the neurochemical and behavioral changes associated with FH using LDL receptor knockout (LDLr-/- ) mice. We noticed that microgliosis was more severe in the hippocampus of middle-aged LDLr-/- mice, which was accompanied by microglial morphological changes and alterations in the immunocontent of synaptic protein markers. At three months of age, the LDLr-/- mice already showed increased microgliosis and decreased immunocontent of claudin-5 in the prefrontal cortex (PFC). Subsequently, 6-month-old male C57BL/6 wild-type and LDLr-/- mice were treated once daily for 30 days with minocycline (a pharmacological inhibitor of microglial cell reactivity) or vehicle (saline). Adult LDLr-/- mice displayed significant hippocampal memory impairment, which was ameliorated by minocycline treatment. Non-treated LDLr-/- mice showed increased microglial density in all hippocampal regions analyzed, a process that was not altered by minocycline treatment. Region-specific microglial morphological analysis revealed different effects of genotype or minocycline treatment on microglial morphology, depending on the hippocampal subregion analyzed. Moreover, 6-month-old LDLr-/- mice exhibited a slight but not significant increase in IBA-1 immunoreactivity in the PFC, which was reduced by minocycline treatment without altering microglial morphology. Minocycline treatment also reduced the presence of microglia within the perivascular area in both the PFC and hippocampus of LDLr-/- mice. However, no significant effects of either genotype or minocycline treatment were observed regarding the phagocytic activity of microglia in the PFC and hippocampus. Our results demonstrate that hippocampal microgliosis, microglial morphological changes, and the presence of these glial cells in the perivascular area, but not increased microglial phagocytic activity, are associated with cognitive deficits in a mouse model of FH.

Olive oil-rich diet during pregnancy/lactation attenuated the early life stress effects on depressive-like behavior and altered energy metabolism in the dorsal hippocampus in a sex-specific manner.

METHODS: and results: Pregnant Wistar rats received diets enriched in soybean oil (SO) or OO during gestation/lactation. At birth, litters were subdivided into MS or intact groups. After weaning, the pups received standard chow until adulthood, when they were subjected to behavioral tasks. At PND90 biochemical analyses were performed. Maternal OO-enriched diet prevented MS-induced higher weight gain, and decreased MS-induced anhedonic behavior. Increased latency to immobility and shorter immobility time were observed in the maternal OO-enrich diet groups. Maternal OO-enrich diet groups also presented reduced reactive oxygen species and increased activity of antioxidant enzymes. In addition, this diet showed sex-specific effects, by decreasing mitochondrial mass and potential, reducing AMPK activation, and increasing synaptophysin and PSD-95 immunocontent in the DH of male rats. Early stress, on the other hand, decreased production of free radicals and decreased levels of SIRT1 in the DH of male rats. In females, OO prevented the anhedonic behavior induced by MS. CONCLUSIONS: Maternal OO-enrich diet attenuated MS-induced depressive behavior in both sexes. In addition, it affected energy metabolism in the DH of male rats, favored synaptic plasticity, and contributed to reducing pathophysiological conditions.

Consumption of a palatable diet rich in simple sugars during development impairs memory of different degrees of emotionality and changes hippocampal plasticity according to the age of the rats.

We investigated the effect of a chronic palatable diet rich in simple sugars on memory of different degrees of emotionality in male adult rats, and on hippocampal plasticity markers in different stages of development. On postnatal day (PND) 21, 45 male Wistar rats were divided in two groups, according to their diet: (1-Control) receiving standard lab chow or (2-Palatable Diet) receiving both standard chow plus palatable diet ad libitum. At PND 60, behavioral tests were performed to investigate memory in distinct tasks. Hippocampal plasticity markers were investigated at PND 28 in half of the animals, and after the behavioral tests. Palatable diet consumption induced an impairment in memory, aversive or not, and increased Na+ , K+ -ATPase activity, both at PND 28, and in the adulthood. Synaptophysin, brain-derived neurotrophic factor (BDNF), and protein kinase B (AKT), and phosphorylated AKT were reduced in the hippocampus at PND 28. However, at PND 75, this diet consumption led to increased hippocampal levels of synaptophysin, spinophilin/neurabin-II, and decreased BDNF and neuronal nitric oxide synthase. These results showed a strongly association of simple sugars-rich diet consumption during the development with memory impairments. Plasticity markers are changed, with results that depend on the stage of development evaluated.

Characterization of advanced glycation end products and their receptor (RAGE) in an animal model of myocardial infarction.

Circulating advanced glycation end products (AGE) and their receptor, RAGE, are increased after a myocardial infarction (MI) episode and seem to be associated with worse prognosis in patients. Despite the increasing importance of these molecules in the course of cardiac diseases, they have never been characterized in an animal model of MI. Thus, the aim of this study was to characterize AGE formation and RAGE expression in plasma and cardiac tissue during cardiac remodeling after MI in rats. Adult male Wistar rats were randomized to receive sham surgery (n = 15) or MI induction (n = 14) by left anterior descending coronary artery ligation. The MI group was stratified into two subgroups based on postoperative left ventricular ejection fraction: low (MIlowEF) and intermediate (MIintermEF). Echocardiography findings and plasma levels of AGEs, protein carbonyl, and free amines were assessed at baseline and 2, 30, and 120 days postoperatively. At the end of follow-up, the heart was harvested for AGE and RAGE evaluation. No differences were observed in AGE formation in plasma, except for a decrease in absorbance in MIlowEF at the end of follow-up. A decrease in yellowish-brown AGEs in heart homogenate was found, which was confirmed by immunodetection of N-ε-carboxymethyl-lysine. No differences could be seen in plasma RAGE levels among the groups, despite an increase in MI groups over the time. However, MI animals presented an increase of 50% in heart RAGE at the end of the follow-up. Despite the inflammatory and oxidative profile of experimental MI in rats, there was no increase in plasma AGE or RAGE levels. However, AGE levels in cardiac tissue declined. Thus, we suggest that the rat MI model should be employed with caution when studying the AGE-RAGE signaling axis or anti-AGE drugs for not reflecting previous clinical findings.

Dietary practices of children and adolescents with Down syndrome.

The aim of this study was to assess dietary intake, breastfeeding history, weight at birth and current weight in children and adolescents with Down syndrome (DS). Therefore, a cross-sectional, controlled study with 19 DS participants and 19 controls without DS matched by gender and age was performed. Except for vitamin D, a lower or the same frequency of insufficient intake in other micronutrients was noted in participants compared with controls. The DS group had a reduced exclusive breastfeeding duration and increased carbohydrate and caloric intake. The consumption of micronutrients in both groups reinforced the current trend of excessive sodium consumption and insufficient intake of calcium, some B complex vitamins and water by children and adolescents.

Lithium and valproate act on the GSK-3ß signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain.

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3ß inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3ß in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3ß levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3ß, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3ß pathway.