Publications (19)91.13 Total impact
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Article: Age-dependent rescue by simvastatin of Alzheimer's disease cerebrovascular and memory deficits.
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ABSTRACT: Alzheimer's disease (AD) is now established as a progressive compromise not only of the neurons but also of the cerebral vasculature. Increasing evidence also indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD, emphasizing the importance to properly control this deficit when aiming for effective therapy. Here, we report that simvastatin (3-6 months, 40 mg/kg/d) completely rescued cerebrovascular reactivity, basal endothelial nitric oxide synthesis, and activity-induced neurometabolic and neurovascular coupling in adult (6 months) and aged (12 months) transgenic mice overexpressing the Swedish and Indiana mutations of the human amyloid precursor protein (AD mice). Remarkably, simvastatin fully restored short- and long-term memory in adult, but not in aged AD mice. These beneficial effects occurred without any decreasing effect of simvastatin on brain amyloid-β (Aβ) levels or plaque load. However, in AD mice with recovered memory, protein levels of the learning- and memory-related immediate early genes c-Fos and Egr-1 were normalized or upregulated in hippocampal CA1 neurons, indicative of restored neuronal function. In contrast, the levels of phospholipase A2, enkephalin, PSD-95, synaptophysin, or glutamate NMDA receptor subunit type 2B were either unaltered in AD mice or unaffected by treatment. These findings disclose new sites of action for statins against Aβ-induced neuronal and cerebrovascular deficits that could be predictive of therapeutic benefit in AD patients. They further indicate that simvastatin and, possibly, other brain penetrant statins bear high therapeutic promise in early AD and in patients with vascular diseases who are at risk of developing AD.Journal of Neuroscience 04/2012; 32(14):4705-15. · 7.11 Impact Factor -
Article: Pyramidal cells and cytochrome P450 epoxygenase products in the neurovascular coupling response to basal forebrain cholinergic input.
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ABSTRACT: Activation of the basal forebrain (BF), the primary source of acetylcholine (ACh) in the cortex, broadly increases cortical cerebral blood flow (CBF), a response downstream to ACh release. Although endothelial nitric oxide and cholinoceptive GABA (γ-aminobutyric acid) interneurons have been implicated, little is known about the role of pyramidal cells in this response and their possible interaction with astrocytes. Using c-Fos immunohistochemistry as a marker of neuronal activation and laser-Doppler flowmetry, we measured changes in CBF evoked by BF stimulation following pharmacological blockade of c-Fos-identified excitatory pathways, astroglial metabolism, or vasoactive mediators. Pyramidal cells including those that express cyclooxygenase-2 (COX-2) displayed c-Fos upregulation. Glutamate acting via NMDA, AMPA, and mGlu receptors was involved in the evoked CBF response, NMDA receptors having the highest contribution (~33%). In contrast, nonselective and selective COX-2 inhibition did not affect the evoked CBF response (+0.4% to 6.9%, ns). The metabolic gliotoxins fluorocitrate and fluoroacetate, the cytochrome P450 epoxygenase inhibitor MS-PPOH and the selective epoxyeicosatrienoic acids (EETs) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) all blocked the evoked CBF response by ~50%. Together, the data demonstrate that the hyperemic response to BF stimulation is largely mediated by glutamate released from activated pyramidal cells and by vasoactive EETs, likely originating from activated astrocytes.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2012; 32(5):896-906. · 5.46 Impact Factor -
Article: Ligand-dependent TrkA activity in brain differentially affects spatial learning and long-term memory.
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ABSTRACT: In the central nervous system, the nerve growth factor (NGF) receptor TrkA is expressed primarily in cholinergic neurons that are implicated in spatial learning and memory, whereas the NGF receptor p75(NTR) is expressed in many neuronal populations and glia. We asked whether selective TrkA activation may have a different impact on learning, short-term memory, and long-term memory. We also asked whether TrkA activation might affect cognition differently in wild-type mice versus mice with cognitive deficits due to transgenic overexpression of mutant amyloid-precursor protein (APP mice). Mice were treated with wild-type NGF (a ligand of TrkA and p75(NTR)) or with selective pharmacological agonists of TrkA that do not bind to p75(NTR). In APP mice, the selective TrkA agonists significantly improved learning and short-term memory. These improvements are associated with a reduction of soluble Aβ levels in the cortex and AKT activation in the cortex and hippocampus. However, this improved phenotype did not translate into improved long-term memory. In normal wild-type mice, none of the treatments affected learning or short-term memory, but a TrkA-selective agonist caused persistent deficits in long-term memory. The deficit in wild-type mice was associated temporally, in the hippocampus, with increased AKT activity, increased brain-derived neurotrophic factor precursor, increased neurotrophin receptor homolog-2 (p75-related protein), and long-term depression. Together, these data indicate that selective TrkA activation affects cognition but does so differently in impaired APP mice versus normal wild-type mice. Understanding mechanisms that govern learning and memory is important for better treatment of cognitive disorders.Molecular pharmacology 05/2011; 80(3):498-508. · 4.53 Impact Factor -
Article: Intact memory in TGF-β1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone.
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ABSTRACT: The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-β1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-β1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-β1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl-L-cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was also administered to pups as a prophylactic 1-year treatment. Elderly TGF mice featured cerebrovascular dysfunction that was not remedied with NAC. In contrast, pioglitazone prevented or reversed this deficit, and rescued the impaired neurovascular coupling response to whisker stimulation, although it failed to normalize the vascular structure. In aged TGF mice, neuronal and cognitive indices--the stimulus-evoked neurometabolic response, cortical cholinergic innervation, and spatial memory in the Morris water maze--were intact. Our findings show that impaired brain hemodynamics and cerebrovascular function are not accompanied by memory impairment in this model. Conceivably in AD, they constitute aggravating factors against a background of aging and underlying pathology. Our data further highlight the ability of pioglitazone to protect the cerebrovasculature marked by TGF-β1 increase, aging, fibrosis, and antioxidant resistance, thus of high relevance for AD patients.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2011; 31(1):200-11. · 5.46 Impact Factor -
Article: Transgenic mice overexpressing APP and transforming growth factor-beta1 feature cognitive and vascular hallmarks of Alzheimer's disease.
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ABSTRACT: High brain levels of amyloid-β (Aβ) and transforming growth factor-β1 (TGF-β1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aβ and TGF-β1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aβ deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aβ- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aβ and TGF-β1 increments.American Journal Of Pathology 11/2010; 177(6):3071-80. · 4.89 Impact Factor -
Article: Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.
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ABSTRACT: Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.Journal of Neuroscience 10/2008; 28(37):9287-96. · 7.11 Impact Factor -
Article: Specific subtypes of cortical GABA interneurons contribute to the neurovascular coupling response to basal forebrain stimulation.
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ABSTRACT: Neurovascular coupling, or the tight coupling between neuronal activity and regional cerebral blood flow (CBF), seems largely driven by the local processing of incoming afferent signals within the activated area. To test if cortical gamma-aminobutyric acid (GABA) interneurons-the local integrators of cortical activity-are involved in this coupling, we stimulated the basalocortical pathway in vivo, monitored cortical CBF, and identified the activated interneurons (c-Fos-immunopositive) and the neuromediators involved in this response. Basal forebrain (BF) stimulation induced ipsilateral increases in CBF and selective activation of layers II to VI somatostatin- and/or neuropeptide Y-containing, as well as layer I GABA interneurons. Nitric oxide synthase interneurons displayed weak bilateral activation, whereas vasoactive intestinal polypeptide- or acetylcholine (ACh)-containing GABA interneurons were not activated. Selective cholinergic deafferentation indicated that ACh released from stimulated BF afferents triggered the CBF response, but the latter was mediated, in part, by the local release of GABA from cholinoceptive cortical interneurons, and through GABA-A receptor-mediated transmission. These data show that activation of specific subsets of GABA interneurons and their GABA-A-mediated effects on neuronal, vascular, and/or astroglial targets are necessary for the full expression of the hemodynamic response to BF stimulation. Further, these findings highlight the importance of understanding the cellular networks and circuitry that underlie hemodynamic signals, as only specific subsets of neurons may be activated by a given stimulus, depending on the afferent inputs they receive and integrate.Journal of Cerebral Blood Flow & Metabolism 03/2008; 28(2):221-31. · 5.01 Impact Factor -
Article: Transforming growth factor-beta 1 impairs endothelin-1-mediated contraction of brain vessels by inducing mitogen-activated protein (MAP) kinase phosphatase-1 and inhibiting p38 MAP kinase.
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ABSTRACT: Brain levels of transforming growth factor-beta1 (TGF-beta1) are increased in Alzheimer's disease and have been implicated in the associated cerebrovascular pathology. We recently reported that transgenic mice that overexpress TGF-beta1 (TGF+ mice) display, with aging, selectively reduced endothelin-1 (ET-1)-mediated contractions. Because ET-1 is a key regulator of cerebrovascular tone and homeostasis, we investigated how increased levels of TGF-beta1 could selectively alter this contractile response. We found that ETA receptors, via activation of p38 mitogen-activated protein (MAP) kinase, mediate the ET-1-induced contraction in mouse cerebral arteries, a response significantly decreased in aged TGF+ mice (-39%; p < 0.01) despite unaltered ETA receptor levels or affinity. In cerebrovascular smooth muscle cell cultures, long-term treatment with TGF-beta1 significantly decreased (>50%; p < 0.05) the ET-1-induced activation of the p38 MAPK/27-kDa heat shock protein (HSP27) signaling pathway. This occurred with no effect upstream to p38 MAP kinase but with the concomitant induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) expression. Inhibition of MKP-1 expression with Ro-31-8220 or suppression of MKP-1 expression by short interfering RNA restored the ET-1-mediated p38 MAP kinase response. These results disclose a new role for long-term increases of TGF-beta1 in modulating cerebrovascular tone by dampening ET-1-mediated activation of the p38 MAPK/HSP27 signaling pathway. Such changes in ET-1-mediated signaling may help maintain vascular wall homeostasis by compensating for the diminished dilatory function induced by TGF-beta1 and amyloid-beta; brain levels of these two molecules are increased in patients with Alzheimer's disease.Molecular pharmacology 12/2007; 72(6):1476-83. · 4.53 Impact Factor -
Chapter: Skeletal and Reproductive Abnormalities in Pth-Null Mice
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ABSTRACT: We have examined the role of parathyroid hormone (PTH) in the postnatal state in a mouse model of PTH-deficiency generated by targeting the Pth gene in ES cells. Mice homozygous for the ablated allele, when maintained on a normal calcium intake, developed hypocalcemia, hyperphosphatemia, and low circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels consistent with primary hypoparathyroidism. Fertility in mutant females was diminished due to abnormal ovarian function manifested in part by impaired angiogenesis in the developing corpus luteum. Even in the presence of ovarian dysfunction, bone turnover was reduced and trabecular and cortical bone volume were increased in PTH-deficient mice. When placed on a low calcium diet, fertility in female mice was completely abolished. Moreover, renal 25-hydroxyvitamin D 1 alpha-hydroocylase (Cyp27bl) expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)2D3 levels, marked osteodastogenesis, and profound bone resorption. These studies demonstrate the dependence of the reproductive and skeletal phenotype in animals with genetically depleted PTH on the external environment as well as on internal hormonal and ionic circulatory factors. They point to the importance of calcium balance in reproduction and show that while PTH action is the first defense against hypocalcemia, 1,25(OH)2D3 can be mobilized, even in the absence of PTH, to guard against extreme calcium deficiency.02/2007: pages 179-196; -
Article: Glutamatergic Control of Microvascular Tone by Distinct GABA Neurons in the Cerebellum.
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ABSTRACT: The tight coupling between increased neuronal activity and local cerebral blood flow, known as functional hyperemia, is essential for normal brain function. However, its cellular and molecular mechanisms remain poorly understood. In the cerebellum, functional hyperemia depends almost exclusively on nitric oxide (NO). Here, we investigated the role of different neuronal populations in the control of microvascular tone by in situ amperometric detection of NO and infrared videomicroscopy of microvessel movements in rat cerebellar slices. Bath application of an NO donor induced both NO flux and vasodilation. Surprisingly, endogenous release of NO elicited by glutamate was accompanied by vasoconstriction that was abolished by inhibition of Ca2+-phopholipase A2 and impaired by cyclooxygenase and thromboxane synthase inhibition and endothelin A receptor blockade, indicating a role for prostanoids and endothelin 1 in this response. Interestingly, direct stimulation of single endothelin 1-immunopositive Purkinje cells elicited constriction of neighboring microvessels. In contrast to glutamate, NMDA induced both NO flux and vasodilation that were abolished by treatment with a NO synthase inhibitor or with tetrodotoxin. These findings indicate that NO derived from neuronal origin is necessary for vasodilation induced by NMDA and, furthermore, that NO-producing interneurons mediate this vasomotor response. Correspondingly, electrophysiological stimulation of single nitrergic stellate cells by patch clamp was sufficient to release NO and dilate both intraparenchymal and upstream pial microvessels. These findings demonstrate that cerebellar stellate and Purkinje cells dilate and constrict, respectively, neighboring microvessels and highlight distinct roles for different neurons in neurovascular coupling.Journal of Neuroscience 07/2006; 26(26):6997-7006. · 7.11 Impact Factor -
Article: Characterization of an RNA granule from developing brain.
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ABSTRACT: In brain, mRNAs are transported from the cell body to the processes, allowing for local protein translation at sites distant from the nucleus. Using subcellular fractionation, we isolated a fraction from rat embryonic day 18 brains enriched for structures that resemble amorphous collections of ribosomes. This fraction was enriched for the mRNA encoding beta-actin, an mRNA that is transported in dendrites and axons of developing neurons. Abundant protein components of this fraction, determined by tandem mass spectrometry, include ribosomal proteins, RNA-binding proteins, microtubule-associated proteins (including the motor protein dynein), and several proteins described only as potential open reading frames. The conjunction of RNA-binding proteins, transported mRNA, ribosomal machinery, and transporting motor proteins defines these structures as RNA granules. Expression of a subset of the identified proteins in cultured hippocampal neurons confirmed that proteins identified in the proteomics were present in neurites associated with ribosomes and mRNAs. Moreover many of the expressed proteins co-localized together. Time lapse video microscopy indicated that complexes containing one of these proteins, the DEAD box 3 helicase, migrated in dendrites of hippocampal neurons at the same speed as that reported for RNA granules. Although the speed of the granules was unchanged by activity or the neurotrophin brain-derived neurotrophic factor, brain-derived neurotrophic factor, but not activity, increased the proportion of moving granules. These studies define the isolation and composition of RNA granules expressed in developing brain.Molecular & Cellular Proteomics 05/2006; 5(4):635-51. · 7.40 Impact Factor -
Article: Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.
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ABSTRACT: The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.Journal of Neuroscience 12/2005; 25(48):11165-74. · 7.11 Impact Factor -
Article: Vascular fibrosis versus amyloid beta (A|[szlig]|)-induced oxidative stress in the cerebrovascular pathology associated with Alzheimer|[rsquo]|s disease (AD)
Journal of Cerebral Blood Flow & Metabolism 07/2005; · 5.01 Impact Factor -
Article: Stellate cells release NO and induce vasodilation of intraparenchymal blood vessels in rat cerebellar slices
Journal of Cerebral Blood Flow & Metabolism 07/2005; · 5.01 Impact Factor -
Article: Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways.
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ABSTRACT: The role of interneurons in neurovascular coupling was investigated by patch-clamp recordings in acute rat cortical slices, followed by single-cell reverse transcriptase-multiplex PCR (RT-mPCR) and confocal observation of biocytin-filled neurons, laminin-stained microvessels, and immunodetection of their afferents by vasoactive subcortical cholinergic (ACh) and serotonergic (5-HT) pathways. The evoked firing of single interneurons in whole-cell recordings was sufficient to either dilate or constrict neighboring microvessels. Identification of vasomotor interneurons by single-cell RT-mPCR revealed expression of vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) in interneurons inducing dilatation and somatostatin (SOM) in those eliciting contraction. Constrictions appeared spatially restricted, maximal at the level of neurite apposition, and were associated with contraction of surrounding smooth muscle cells, providing the first evidence for neural regulation of vascular sphincters. Direct perfusion of VIP and NO donor onto the slices dilated microvessels, whereas neuropeptide Y (NPY) and SOM induced vasoconstriction. RT-PCR analyses revealed expression of specific subtypes of neuropeptide receptors in smooth muscle cells from intracortical microvessels, compatible with the vasomotor responses they elicited. By triple and quadruple immunofluorescence, the identified vasomotor interneurons established contacts with local microvessels and received, albeit to a different extent depending on interneuron subtypes, somatic and dendritic afferents from ACh and 5-HT pathways. Our results demonstrate the ability of specific subsets of cortical GABA interneurons to transmute neuronal signals into vascular responses and further suggest that they could act as local integrators of neurovascular coupling for subcortical vasoactive pathways.Journal of Neuroscience 11/2004; 24(41):8940-9. · 7.11 Impact Factor -
Article: Skeletal abnormalities in Pth-null mice are influenced by dietary calcium.
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ABSTRACT: We have examined the role of PTH in the postnatal state in a mouse model of PTH deficiency generated by targeting the Pth gene in embryonic stem cells. Mice homozygous for the ablated allele, when maintained on a normal calcium intake, developed hypocalcemia, hyperphosphatemia, and low circulating 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels consistent with primary hypoparathyroidism. Bone turnover was reduced, leading to increased trabecular and cortical bone volume in PTH-deficient mice. When mutant mice were placed on a low-calcium diet, renal 25-hydroxyvitamin D 1 alpha-hydroxylase expression increased despite the absence of PTH, leading to a rise in circulating 1,25(OH)(2)D(3) levels, marked osteoclastogenesis, and profound bone resorption. These studies demonstrate the dependence of the skeletal phenotype in animals with genetically depleted PTH on the external environment as well as on internal hormonal and ionic circulatory factors. They also show that, although PTH action is the first defense against hypocalcemia, 1,25(OH)(2)D(3) can be mobilized, even in the absence of PTH, to guard against extreme calcium deficiency.Endocrinology 05/2004; 145(4):2046-53. · 4.46 Impact Factor -
Article: GABA neurons provide a rich input to microvessels but not nitric oxide neurons in the rat cerebral cortex: A means for direct regulation of local cerebral blood flow
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ABSTRACT: Basal forebrain neurons project to microvessels and the somata of nitric oxide (NO) synthase-containing neurons in the cerebral cortex, and their stimulation results in increases in cortical perfusion. γ-Aminobutyric acid (GABA) is the second major neurotransmitter synthesized by these neurons and it has also been reported to modify cerebromicrovascular tone. We thus investigated by light and electron microscopy the association of GABA neurons (labeled for glutamic acid decarboxylase [GAD]) with cortical microvessels and/or NO neurons (identified by nicotinamide adenine dinucleotide [NADPH-D] histochemistry) within the frontoparietal and perirhinal cerebral cortex in the rat. On thick and semithin sections, a high density of GAD puncta was observed, several surrounded intracortical blood vessels and neuronal perikarya. In contrast, NADPH-D cell somata and proximal dendrites were only occasionally contacted by GAD nerve terminals. Perivascular and perisomatic GAD appositions were identified at the ultrastructural level as large (0.44–0.50 μm2) neuronal varicosities located in the immediate vicinity of, or being directly apposed to, vessels or unstained neuronal cell bodies. In both cortical areas, perivascular GAD terminals were located at about 1 μm from the vessels and were seen to frequently establish junctional contacts (synaptic frequency of 25–40% in single thin sections) with adjacent neuronal but not vascular elements. Ibotenic or quisqualic acid lesion of the substantia innominata did not significantly affect the density of cortical and perivascular GAD terminals, suggesting that they mostly originated locally in the cortex. These results suggest that GABA terminals can interact directly with the microvascular bed and that the somata and proximal dendrites of NO neurons are not a major target for cortical GABA neurotransmission. However, based on the colocalization of GABA and NADPH-D in a subset of cortical neurons, we suggest that these interneurons could be implicated in the cortical vascular response elicited by stimulation of basal forebrain neurons. J. Comp. Neurol. 421:161–171, 2000. © 2000 Wiley-Liss, Inc.The Journal of Comparative Neurology 05/2000; 421(2):161 - 171. · 3.81 Impact Factor -
Article: Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice
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ABSTRACT: Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Aβ) levels and the number of Aβ plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Aβ plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.Neurobiology of Disease. -
Article: Reversal of fully developed cerebrovascular dysfunctions in two transgenic mouse models of Alzheimer's disease
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Institutions
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2000–2012
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McGill University
Montréal, Quebec, Canada
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2004
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French National Centre for Scientific Research
Lyon, Rhone-Alpes, France
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