The Experts below are selected from a list of 2085 Experts worldwide ranked by ideXlab platform
John R Cirrito - One of the best experts on this subject based on the ideXlab platform.
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effect of escitalopram on aβ levels and plaque load in an alzheimer mouse model
Neurology, 2020Co-Authors: John R Cirrito, Jinmoo Lee, Clare E Wallace, Ping Yan, Todd A Davis, Woodrow D Gardiner, Brookelyn M Doherty, Diana King, Carla M Yuede, Yvette I ShelineAbstract:Background Several neurotransmitter receptors activate signaling pathways that alter processing of the amyloid precursor protein (APP) into β-amyloid (Aβ). Serotonin signaling through a subset of serotonin receptors suppresses Aβ generation. We proposed that escitalopram, the most specific selective serotonin reuptake inhibitor (SSRI) that inhibits the serotonin transporter SERT, would suppress Aβ levels in mice. Objectives We hypothesized that acute treatment with escitalopram would reduce Aβ generation, which would be reflected chronically with a significant reduction in Aβ plaque load. Methods We performed in vivo microdialysis and in vivo 2-photon imaging to assess changes in Brain Interstitial Fluid (ISF) Aβ and Aβ plaque size over time, respectively, in the APP/presenilin 1 mouse model of Alzheimer disease treated with vehicle or escitalopram. We also chronically treated mice with escitalopram to determine the effect on plaques histologically. Results Escitalopram acutely reduced ISF Aβ by 25% by increasing α-secretase cleavage of APP. Chronic administration of escitalopram significantly reduced plaque load by 28% and 34% at 2.5 and 5 mg/d, respectively. Escitalopram at 5 mg/kg did not remove existing plaques, but completely arrested individual plaque growth over time. Conclusions Escitalopram significantly reduced Aβ in mice, similar to previous findings in humans treated with acute dosing of an SSRI.
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the sleep wake cycle regulates Brain Interstitial Fluid tau in mice and csf tau in humans
Science, 2019Co-Authors: Jerrah K Holth, John R Cirrito, Thomas E Mahan, Mary Beth Finn, Sarah K Fritschi, Chanung Wang, Nigel P Pedersen, Melissa Manis, Joel C Geerling, Patrick M FullerAbstract:The sleep-wake cycle regulates Interstitial Fluid (ISF) and cerebrospinal Fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.
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redundant gs coupled serotonin receptors regulate amyloid β metabolism in vivo
Molecular Neurodegeneration, 2016Co-Authors: Jonathan R Fisher, Clare E Wallace, Yvette I Sheline, Danielle L Tripoli, John R CirritoAbstract:Background The aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer’s disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the Brain Interstitial Fluid (ISF) in a mouse model of AD and in the cerebrospinal Fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction.
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neuronal heparan sulfates promote amyloid pathology by modulating Brain amyloid β clearance and aggregation in alzheimer s disease
Science Translational Medicine, 2016Co-Authors: Na Zhao, John R Cirrito, David M Holtzman, Guojun Bu, Yu Yamaguchi, Takahisa KanekiyoAbstract:Accumulation of amyloid-β (Aβ) peptide in the Brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the Brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the Brain Interstitial Fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human Brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.
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neuronal heparan sulfates promote amyloid pathology by modulating Brain amyloid β clearance and aggregation in alzheimer s disease
Science Translational Medicine, 2016Co-Authors: Chia Chen Liu, John R Cirrito, Na Zhao, Yu Yamaguchi, Takahisa Kanekiyo, David M HoltzmanAbstract:Accumulation of amyloid-β (Aβ) peptide in the Brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the Brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the Brain Interstitial Fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human Brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.
David M Holtzman - One of the best experts on this subject based on the ideXlab platform.
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neuronal heparan sulfates promote amyloid pathology by modulating Brain amyloid β clearance and aggregation in alzheimer s disease
Science Translational Medicine, 2016Co-Authors: Na Zhao, John R Cirrito, David M Holtzman, Guojun Bu, Yu Yamaguchi, Takahisa KanekiyoAbstract:Accumulation of amyloid-β (Aβ) peptide in the Brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the Brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the Brain Interstitial Fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human Brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.
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neuronal heparan sulfates promote amyloid pathology by modulating Brain amyloid β clearance and aggregation in alzheimer s disease
Science Translational Medicine, 2016Co-Authors: Chia Chen Liu, John R Cirrito, Na Zhao, Yu Yamaguchi, Takahisa Kanekiyo, David M HoltzmanAbstract:Accumulation of amyloid-β (Aβ) peptide in the Brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the Brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the Brain Interstitial Fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human Brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.
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effects of growth hormone releasing hormone on sleep and Brain Interstitial Fluid amyloid β in an app transgenic mouse model
Brain Behavior and Immunity, 2015Co-Authors: Fan Liao, Hong Jiang, Thomas E Mahan, Tony J Zhang, David M HoltzmanAbstract:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the Brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the Brain Interstitial Fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects Brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition.
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amyloid β dynamics are regulated by orexin and the sleep wake cycle
Science, 2009Co-Authors: Jaeeun Kang, Miranda M Lim, Randall J Bateman, James J Lee, Liam P Smyth, John R Cirrito, Nobuhiro Fujiki, Seiji Nishino, David M HoltzmanAbstract:Amyloid-beta (Abeta) accumulation in the Brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in Brain Interstitial Fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.
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amyloid β dynamics correlate with neurological status in the injured human Brain
Science, 2008Co-Authors: David L Brody, Sandra Magnoni, Kate E Schwetye, Michael L Spinner, Thomas J Esparza, N Stocchetti, Gregory J Zipfel, David M HoltzmanAbstract:The amyloid-β peptide (Aβ) plays a central pathophysiological role in Alzheimer's disease, but little is known about the concentration and dynamics of this secreted peptide in the extracellular space of the human Brain. We used intracerebral microdialysis to obtain serial Brain Interstitial Fluid (ISF) samples in 18 patients who were undergoing invasive intracranial monitoring after acute Brain injury. We found a strong positive correlation between changes in Brain ISF Aβ concentrations and neurological status, with Aβ concentrations increasing as neurological status improved and falling when neurological status declined. Brain ISF Aβ concentrations were also lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentration.
Ingrid L Kwee - One of the best experts on this subject based on the ideXlab platform.
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Fluid dynamics inside the Brain barrier current concept of Interstitial flow glymphatic flow and cerebrospinal Fluid circulation in the Brain
The Neuroscientist, 2019Co-Authors: Tsutomu Nakada, Ingrid L KweeAbstract:The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of Brain Fluid dynamics. The Brain is protected by barriers preventing free access of systemic Fluid. The same barrier system, however, also isolates Brain Interstitial Fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic Interstitial Fluid circulation, cannot be propagated to the Interstitial Fluid compartment of the Brain. Without a proper alternative mechanism, Brain Interstitial Fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for Interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate Interstitial Fluid motion. Interstitial flow in peri-arterial VRS constitutes an essential part of the clearance system for β-amyloid, whereas Interstitial flow in peri-venous VRS creates bulk Interstitial Fluid flow, which, together with the choroid plexus, creates the necessary ventricular cerebrospinal Fluid (CSF) volume for proper CSF circulation.
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Fluid dynamics inside the Brain barrier current concept of Interstitial flow glymphatic flow and cerebrospinal Fluid circulation in the Brain
The Neuroscientist, 2019Co-Authors: Tsutomu Nakada, Ingrid L KweeAbstract:The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of Brain Fluid dynamics. The Brain is protected by barriers preventing free access of systemic Fluid. The same barrier system, however, also isolates Brain Interstitial Fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic Interstitial Fluid circulation, cannot be propagated to the Interstitial Fluid compartment of the Brain. Without a proper alternative mechanism, Brain Interstitial Fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for Interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate Interstitial...
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aquaporin 4 functionality and virchow robin space water dynamics physiological model for neurovascular coupling and glymphatic flow
International Journal of Molecular Sciences, 2017Co-Authors: Tsutomu Nakada, Ingrid L Kwee, Hironaka Igarashi, Yuji SuzukiAbstract:The unique properties of Brain capillary endothelium, critical in maintaining the blood-Brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on Fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying Brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for Interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the Interstitial Fluid inside the BBB by the tightly sealed endothelium of Brain capillaries. Instead, Fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (Interstitial) Fluid. Brain Interstitial Fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the Brain equivalent of systemic lymphatics.
Tsutomu Nakada - One of the best experts on this subject based on the ideXlab platform.
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Fluid dynamics inside the Brain barrier current concept of Interstitial flow glymphatic flow and cerebrospinal Fluid circulation in the Brain
The Neuroscientist, 2019Co-Authors: Tsutomu Nakada, Ingrid L KweeAbstract:The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of Brain Fluid dynamics. The Brain is protected by barriers preventing free access of systemic Fluid. The same barrier system, however, also isolates Brain Interstitial Fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic Interstitial Fluid circulation, cannot be propagated to the Interstitial Fluid compartment of the Brain. Without a proper alternative mechanism, Brain Interstitial Fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for Interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate Interstitial Fluid motion. Interstitial flow in peri-arterial VRS constitutes an essential part of the clearance system for β-amyloid, whereas Interstitial flow in peri-venous VRS creates bulk Interstitial Fluid flow, which, together with the choroid plexus, creates the necessary ventricular cerebrospinal Fluid (CSF) volume for proper CSF circulation.
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Fluid dynamics inside the Brain barrier current concept of Interstitial flow glymphatic flow and cerebrospinal Fluid circulation in the Brain
The Neuroscientist, 2019Co-Authors: Tsutomu Nakada, Ingrid L KweeAbstract:The discovery of the water specific channel, aquaporin, and abundant expression of its isoform, aquaporin-4 (AQP-4), on astrocyte endfeet brought about significant advancements in the understanding of Brain Fluid dynamics. The Brain is protected by barriers preventing free access of systemic Fluid. The same barrier system, however, also isolates Brain Interstitial Fluid from the hydro-dynamic effect of the systemic circulation. The systolic force of the heart, an essential factor for proper systemic Interstitial Fluid circulation, cannot be propagated to the Interstitial Fluid compartment of the Brain. Without a proper alternative mechanism, Brain Interstitial Fluid would stay stagnant. Water influx into the peri-capillary Virchow-Robin space (VRS) through the astrocyte AQP-4 system compensates for this hydrodynamic shortage essential for Interstitial flow, introducing the condition virtually identical to systemic circulation, which by virtue of its fenestrated capillaries creates appropriate Interstitial...
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aquaporin 4 functionality and virchow robin space water dynamics physiological model for neurovascular coupling and glymphatic flow
International Journal of Molecular Sciences, 2017Co-Authors: Tsutomu Nakada, Ingrid L Kwee, Hironaka Igarashi, Yuji SuzukiAbstract:The unique properties of Brain capillary endothelium, critical in maintaining the blood-Brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on Fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying Brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for Interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the Interstitial Fluid inside the BBB by the tightly sealed endothelium of Brain capillaries. Instead, Fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (Interstitial) Fluid. Brain Interstitial Fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the Brain equivalent of systemic lymphatics.
Berislav V Zlokovic - One of the best experts on this subject based on the ideXlab platform.
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Pericyte loss influences Alzheimer-like neurodegeneration in mice
Nature Communications, 2013Co-Authors: Abhay P. Sagare, Qingyi Ma, Anita Ramanathan, Robert D Bell, Ethan A Winkler, Zhen Zhao, Berislav V ZlokovicAbstract:Pericytes are cells in the blood-Brain barrier that degenerate in Alzheimer's disease (AD), a neurological disorder associated with neurovascular dysfunction, abnormal elevation of amyloid β-peptide (Aβ), tau pathology and neuronal loss. Whether pericyte degeneration can influence AD-like neurodegeneration and contribute to disease pathogenesis remains, however, unknown. Here we show that in mice overexpressing Aβ-precursor protein, pericyte loss elevates Brain Aβ40 and Aβ42 levels and accelerates amyloid angiopathy and cerebral β-amyloidosis by diminishing clearance of soluble Aβ40 and Aβ42 from Brain Interstitial Fluid prior to Aβ deposition. We further show that pericyte deficiency leads to the development of tau pathology and an early neuronal loss that is normally absent in Aβ-precursor protein transgenic mice, resulting in cognitive decline. Our data suggest that pericytes control multiple steps of AD-like neurodegeneration pathogenic cascade in Aβ-precursor protein-overexpressing mice. Therefore, pericytes may represent a novel therapeutic target to modify disease progression in AD.
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low density lipoprotein receptor overexpression enhances the rate of Brain to blood aβ clearance in a mouse model of β amyloidosis
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Joseph M Castellano, Rashid Deane, Philip B Verghese, Ronald B Demattos, Floy R Stewart, Tim West, Andrew J Gottesdiener, Andrew C Paoletti, Tristan Kasper, Berislav V ZlokovicAbstract:The apolipoprotein E (APOE)-e4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the Brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Aβ accumulation by altering Aβ clearance from Brain Interstitial Fluid. We hypothesized that increasing LDLR levels enhances blood–Brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the Brain Aβ efflux index method, we found that blood–Brain barrier-mediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the Brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances Brain-to-blood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates Brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the Brain.
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Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin bound and free iron into the rat Brain
Journal of Neurochemistry, 2004Co-Authors: Rashid Deane, Wei Zheng, Berislav V ZlokovicAbstract:Iron transport into the CNS is still not completely understood. Using a Brain perfusion technique in rats, we have shown a significant Brain capillary uptake of circulating transferrin (Tf)-bound and free 59Fe (1 nm) at rates of 136 +/- 26 and 182 +/- 23 microL/g/min, respectively, while their respective transport rates into Brain parenchyma were 1.68 +/- 0.56 and 1.52 +/- 0.48 microL/g/min. Regional Tf receptor density (Bmax) in Brain endothelium determined with 125I-holo-Tf correlated well with 59Fe-Tf regional Brain uptake rates reflecting significant vascular association of iron. Tf-bound and free circulating 59Fe were sequestered by the choroid plexus and transported into the CSF at low rates of 0.17 +/- 0.01 and 0.09 +/- 0.02 microL/min/g, respectively, consistent with a 10-fold Brain-CSF concentration gradient for 59Fe, Tf-bound or free. We conclude that transport of circulating Tf-bound and free iron could be equally important for its delivery to the CNS. Moreover, data suggest that entry of Tf-bound and free iron into the CNS is determined by (i) its initial sequestration by Brain capillaries and choroid plexus, and (ii) subsequent controlled and slow release from vascular structures into Brain Interstitial Fluid and CSF.
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Brain clearance of alzheimer s amyloid β40 in the squirrel monkey a spect study in a primate model of cerebral amyloid angiopathy
Journal of Drug Targeting, 2002Co-Authors: James R Bading, Shinya Yamada, Jasmina B Mackic, Linda Kirkman, Carol A Miller, Miguel Calero, Jorge Ghiso, Blas Frangione, Berislav V ZlokovicAbstract:Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid- β 40 peptide (A β 40) crosses the blood-Brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123 I-A β 40 and 99m Tc-DTPA, an extracellular marker, from the Brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity Brain clearance curves indicated bi-exponential removal of 123 I-A β 40 with an initial rapid washout (1.1 ≤ t 1/2 ≤ 2.7 h). This, plus the observed appearance of 123 I-radioactivity in plasma suggest significant Brain-to-blood transport. In contrast, 99m Tc-DTPA was removed slowly by Brain Interstitial Fluid bulk flow (monoexponential decay with 6.8 ≤ t 1/2 ≤ 16.8 h) . A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old)...