A Novel Neurovascular Liaison Governing the Blood-Brain Barrier.

How circulating signals enter the median eminence to trigger homeostatic hypothalamic responses is not well understood. Jiang et al. describe a neural mechanism that increases endothelial fenestrations and enhances the hypothalamic response to the circulating hormone leptin, suggesting a novel way to regulate brain entry through vascular wall remodeling.

Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury.

BACKGROUND AND PURPOSE: Ischemic brain injury is characterized by 2 temporally distinct but interrelated phases: ischemia (primary energy failure) and reperfusion (secondary energy failure). Loss of cerebral blood flow leads to decreased oxygen levels and energy crisis in the ischemic area, initiating a sequence of pathophysiological events that after reoxygenation lead to ischemia/reperfusion (I/R) brain damage. Mitochondrial impairment and oxidative stress are known to be early events in I/R injury. However, the biochemical mechanisms of mitochondria damage in I/R are not completely understood. METHODS: We used a mouse model of transient focal cerebral ischemia to investigate acute I/R-induced changes of mitochondrial function, focusing on mechanisms of primary and secondary energy failure. RESULTS: Ischemia induced a reversible loss of flavin mononucleotide from mitochondrial complex I leading to a transient decrease in its enzymatic activity, which is rapidly reversed on reoxygenation. Reestablishing blood flow led to a reversible oxidative modification of mitochondrial complex I thiol residues and inhibition of the enzyme. Administration of glutathione-ethyl ester at the onset of reperfusion prevented the decline of complex I activity and was associated with smaller infarct size and improved neurological outcome, suggesting that decreased oxidation of complex I thiols during I/R-induced oxidative stress may contribute to the neuroprotective effect of glutathione ester. CONCLUSIONS: Our results unveil a key role of mitochondrial complex I in the development of I/R brain injury and provide the mechanistic basis for the well-established mitochondrial dysfunction caused by I/R. Targeting the functional integrity of complex I in the early phase of reperfusion may provide a novel therapeutic strategy to prevent tissue injury after stroke.

Metabolic and Non-Cognitive Manifestations of Alzheimer's Disease: The Hypothalamus as Both Culprit and Target of Pathology.

Alzheimer's disease (AD) is increasingly recognized as a complex neurodegenerative disease beginning decades prior to the cognitive decline. While cognitive deficits remain the cardinal manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in body weight and neuroendocrine functions, are also present, often preceding the cognitive decline. Furthermore, hypothalamic dysfunction can also be a driver of AD pathology. Here we offer a brief appraisal of hypothalamic dysfunction in AD and provide insight into an underappreciated dual role of the hypothalamus as both a culprit and target of AD pathology, as well as into new opportunities for therapeutic interventions and biomarker development.

Female protection from slow-pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors.

Renin­angiotensin system overactivity, upregulation of postsynaptic NMDA receptor function, and increased reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) are hallmarks of angiotensin II (AngII)-induced hypertension, which is far more common in young males than in young females. We hypothesize that the sex differences in hypertension are related to differential AngII-induced changes in postsynaptic trafficking of the essential NMDA receptor GluN1 subunit and ROS production in PVN cells expressing angiotensin Type 1a receptor (AT1aR). We tested this hypothesis using slow-pressor (14-day) infusion of AngII (600 ng/kg/min) in mice, which elicits hypertension in males but not in young females. Two-month-old male and female transgenic mice expressing enhanced green fluorescent protein (EGFP) in AT1aR-containing cells were used. In males, but not in females, AngII increased blood pressure and ROS production in AT1aR­EGFP PVN cells at baseline and following NMDA treatment. Electron microscopy showed that AngII increased cytoplasmic and total GluN1­silver-intensified immunogold (SIG) densities and induced a trend toward an increase in near plasmalemmal GluN1­SIG density in AT1aR­EGFP dendrites of males and females. Moreover, AngII decreased dendritic area and diameter in males, but increased dendritic area of small (<1 µm) dendrites and decreased diameter of large (>1 µm) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor ß do not colocalize, suggesting that if estrogen is involved, its effect is indirect. These data suggest that the sexual dimorphism in AngII-induced hypertension is associated with sex differences in ROS production in AT1aR-containing PVN cells but not with postsynaptic NMDA receptor trafficking.

Transgenic mice overexpressing amyloid precursor protein exhibit early metabolic deficits and a pathologically low leptin state associated with hypothalamic dysfunction in arcuate neuropeptide Y neurons.

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-ß (Aß) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aß. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aß can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aß accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aß.

Angiotensin II-induced hypertension differentially affects estrogen and progestin receptors in central autonomic regulatory areas of female rats.

Estrogen receptor (ER) activation in central autonomic nuclei modulates arterial blood pressure (ABP) and counteracts the deleterious effect of hypertension. We tested the hypothesis that hypertension, in turn, influences the expression and trafficking of gonadal steroid receptors in central cardiovascular circuits. Thus, we examined whether ER- and progestin receptor (PR)-immunoreactivity (ir) are altered in medullary and hypothalamic autonomic areas of cycling rats following chronic infusion of the hypertensive agent, angiotensin II (AngII). After 1 week AngII-infusion, systolic ABP was elevated from 103+/-4 to 172+/-8 mmHg (p<0.05; N=8/group) and all rats were in diestrus (low estrogen). In AngII-infused rats the number of PR-immunoreactive nuclei was reduced (-72%) compared to saline-infused controls also in diestrus (p<0.05). Furthermore, the intensity of ERalpha-ir increased selectively in nuclei (16%) and cytoplasm (21%) of cells in the commissural nucleus of the solitary tract (cNTS; p<0.05) while neither the number nor intensity of ERbeta-labeled cells changed (p>0.05). Following chronic AngII-infusion, electron microscopy showed a higher cytoplasmic-to-nuclear ratio of ERalpha-labeling selectively in tyrosine hydroxylase (TH)-labeled neurons in the cNTS. Furthermore, AngII-infusion increased ERalpha-ir in the cytosol of TH- and non-TH neuronal perikarya and increased the amount of ERalpha-ir associated with endoplasmic reticulum only in TH-containing perikarya. The data suggest that hypertension modulates the expression and subcellular distribution of ERalpha and PR in central autonomic regions involved in blood pressure control. Considering that ERalpha counteracts the central and peripheral effects of AngII, these receptor changes may underlie adaptive responses that protect females from the deleterious effects of hypertension.