Navegando por Autor "Bem, Andreza Fabro de"
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Item High cholesterol diet exacerbates blood-brain barrier disruption in LDLr–/– mice : impact on cognitive function.(2020) Oliveira, Jade de; Engel, Daiane Fátima; Paula, Gabriela Cristina de; Godoi, Danúbia Bonfanti dos Santos de; Lopes, Jadna Bogado; Farina, Marcelo; Moreira, Eduardo Luiz Gasnhar; Bem, Andreza Fabro deBackground: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/– mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/– mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. Results: A tenfold elevation in plasma cholesterol levels of LDLr–/– mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/– mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/– mice treated with a hypercholesterolemic diet. The LDLr–/– mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/– mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr–/– mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations.Item Hippocampal function is impaired by a short-term high-fat diet in mice : increased blood–brain barrier permeability and neuroinflammation as triggering events.(2021) Paula, Gabriela Cristina de; Brunetta, Henver Simionato; Engel, Daiane Fátima; Gaspar, Joana Margarida Navalho; Velloso, Licio Augusto; Engblom, David; Oliveira, Jade de; Bem, Andreza Fabro deWorldwide, and especially in Western civilizations, most of the staple diets contain high amounts of fat and refined carbohydrates, leading to an increasing number of obese individuals. In addition to inducing metabolic disorders, energy dense food intake has been suggested to impair brain functions such as cognition and mood control. Here we demonstrate an impaired memory function already 3 days after the start of a high-fat diet (HFD) exposure, and depressive-like behavior, in the tail suspension test, after 5 days. These changes were followed by reduced synaptic density, changes in mitochondrial function and astrocyte activation in the hippocampus. Preceding or coinciding with the behavioral changes, we found an induction of the proinflammatory cytokines TNF-α and IL-6 and an increased permeability of the blood–brain barrier (BBB), in the hippocampus. Finally, in mice treated with a TNF-α inhibitor, the behavioral and BBB alterations caused by HFD-feeding were mitigated suggesting that inflammatory signaling was critical for the changes. In summary, our findings suggest that HFD rapidly triggers hippocampal dysfunction associated with BBB disruption and neuroinflammation, promoting a progressive breakdown of synaptic and metabolic function. In addition to elucidating the link between diet and cognitive function, our results might be relevant for the comprehension of the neurodegenerative process.Item Mitochondrial NAD(P)+ transhydrogenase is unevenly distributed in different brain regions, and its loss causes depressive-like behavior and motor dysfunction in mice.(2020) Francisco, Annelise; Engel, Daiane Fátima; Figueira, Tiago Rezende; Rogério, Fábio; Bem, Andreza Fabro de; Castilho, Roger FrigérioAbstract—NAD(P)+ transhydrogenase (NNT) links redox states of the mitochondrial NAD(H) and NADP(H) via a reaction coupled to proton-motive force across the inner mitochondrial membrane. NNT is believed to be ubiqui- tously present in mammalian cells, but its expression may vary substantially in different tissues. The present study investigated the tissue distribution and possible roles of NNT in the mouse brain. The pons exhibited high NNT expression/activity, and immunohistochemistry revealed intense NNT labeling in neurons from brainstem nuclei. In some of these regions, neuronal NNT labeling was strongly colocalized with enzymes involved in the biosynthesis of 5-hydroxytryptamine (5-HT) and nitric oxide ( NO), which directly or indirectly require NADPH. Behavioral tests were performed in mice lacking NNT activity (Nnt/, mice carrying the mutated NntC57BL/6J allele from the C57BL/6J strain) and the Nnt+/+ controls. Our data demonstrated that aged Nnt/ mice (18–20 months old), but not adult mice (3–4 months old), showed an increased immobility time in the tail suspension test that was reversed by fluoxetine treatment, providing evidence of depressive-like behavior in these mice. Aged Nnt/ mice also exhibited behavioral changes and impaired locomotor activity in the open field and rotarod tests. Despite the colocalization between NNT and NO synthase, the S-nitrosation and cGMP levels were independent of the Nnt genotype. Taken together, our results indicated that NNT is unevenly distributed throughout the brain and asso- ciated with 5-THergic and NOergic neurons. The lack of NNT led to alterations in brain functions related to mood and motor behavior/performance in aged mice.