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1.
Neuroreport ; 30(9): 619-627, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31045849

RESUMO

Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to transient but significant reduction in available oxygen. The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a regulatory mediator of a wide spectrum of genes involved in metabolism, synaptogenesis, and blood flow. The purpose of this study was to begin to explore the potential relationship between exercise in the form of running on a motorized treadmill and the activation of genes involved in exercise-dependent neuroplasticity to begin to elucidate the underlying molecular mechanisms involved. Mice were subjected to treadmill exercise and striatal tissues analyzed with a commercial microarray designed to identify transcripts whose expression is altered by exposure to hypoxia, a condition occurring in cells under a high metabolic demand. Several candidate genes were identified, and a subset involved in metabolism and angiogenesis were selected to elucidate their temporal and regional patterns of expression with exercise. Transcript analysis included Hif1a (hypoxia-inducible factor 1α), Ldha (lactate dehydrogenase A), Slc2a1 (glucose transporter 1), Slc16a1 (monocarboxylate transporter 1), Slc16a7 (monocarboxylate transporter 2), and Vegf (vascular endothelial growth factor). Overall these results indicate that several genes involved in the elevated metabolic response with exercise are consistent with increased expression of HIF-1α suggesting a regulatory role for HIF-1α in exercise-enhanced neuroplasticity. Furthermore, these increases in gene expression appear regionally specific; occurring with brain regions we have previously shown to be sites for increased cerebral blood flow with activity. Such findings are beginning to lay down a working hypothesis that specific forms of exercise lead to circuit specific neuronal activation and can identify a potentially novel therapeutic approach to target dysfunctional behaviors subserved by such circuitry.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Geroscience ; 39(5-6): 499-550, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29270905

RESUMO

A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, "healthspan," "lifespan," and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as "Adaptive Homeostasis" (Davies Mol Asp Med 49:1-7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573-2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.


Assuntos
Adaptação Fisiológica , Envelhecimento/genética , Dieta Rica em Proteínas/estatística & dados numéricos , Hipercolesterolemia/epidemiologia , Estresse Oxidativo/fisiologia , Oxigênio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Feminino , França , Radicais Livres/metabolismo , Avaliação Geriátrica , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco
4.
J Cereb Blood Flow Metab ; 36(1): 216-27, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25757756

RESUMO

The blood­brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer's disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA­MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Barreira Hematoencefálica/patologia , Pericitos/patologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo , Contagem de Células , Estudos de Coortes , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Pericitos/metabolismo , Isoformas de Proteínas
5.
Neuron ; 85(2): 296-302, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25611508

RESUMO

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.


Assuntos
Envelhecimento/metabolismo , Barreira Hematoencefálica/metabolismo , Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Disfunção Cognitiva/metabolismo , Giro Denteado/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/líquido cefalorraquidiano , Encéfalo/metabolismo , Estudos de Casos e Controles , Núcleo Caudado/metabolismo , Córtex Cerebral/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neostriado/metabolismo , Pericitos/metabolismo , Permeabilidade , Albumina Sérica , Tálamo/metabolismo , Adulto Jovem
6.
Nat Neurosci ; 18(7): 978-87, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26005850

RESUMO

PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-ß (Aß) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aß clearance across the murine blood-brain barrier (BBB) and accelerated Aß pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aß bound to the low density lipoprotein receptor related protein-1, a key Aß clearance receptor, and guided Aß trafficking to Rab5 and Rab11, leading to Aß endothelial transcytosis and clearance. PICALM levels and Aß clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aß clearance. Thus, PICALM regulates Aß BBB transcytosis and clearance, which has implications for Aß brain homeostasis and clearance therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Córtex Cerebral/metabolismo , Proteínas Monoméricas de Montagem de Clatrina/metabolismo , Animais , Capilares/metabolismo , Endotélio Vascular/metabolismo , Homeostase , Humanos , Taxa de Depuração Metabólica , Camundongos , Camundongos Knockout , Proteínas Monoméricas de Montagem de Clatrina/deficiência , Células-Tronco Pluripotentes , Transcitose
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