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  1. AU="Philbert, Sasha A"
  2. AU=Ruan Jue
  3. AU=Koo J Y M AU=Koo J Y M
  4. AU="Ouni, Ala"
  5. AU="Tseng, Li-Wen" AU="Tseng, Li-Wen"
  6. AU="Riemenschneider, G." AU="Riemenschneider, G."
  7. AU="Wessel, Connor"
  8. AU=Chu Xiaogang
  9. AU="Moulding, David J"
  10. AU=Ogawa Makio
  11. AU="Heisel, Curtis J"
  12. AU="Zakharchenko, Artem"
  13. AU="C.K.Cheong, "
  14. AU="Pierfrancesco Franco"
  15. AU="Barutcu, Sezgin"
  16. AU="Saha, Titas"
  17. AU="Lipina, Tatiana V"
  18. AU="Herman, Mariana"
  19. AU="Sicard, Delphine"
  20. AU="Guglielmi, Adele"
  21. AU="Hammond, Ester"
  22. AU="Li, Lanhui"
  23. AU="Hassett, Michael J"
  24. AU="Kyle K. Biggar"
  25. AU="Al-Garawi, Amal"
  26. AU="Freeman, Willard M"
  27. AU="Lussier, A M"
  28. AU="J.Castaneda, "
  29. AU="Izquierdo, Ledys"
  30. AU="Werner, F"
  31. AU="Boddington, Marie E"
  32. AU="N Siddaiah"

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  1. Artikel: Extensive multiregional urea elevations in a case-control study of vascular dementia point toward a novel shared mechanism of disease amongst the age-related dementias.

    Philbert, Sasha A / Xu, Jingshu / Scholefield, Melissa / Patassini, Stefano / Church, Stephanie J / Unwin, Richard D / Roncaroli, Federico / Cooper, Garth J S

    Frontiers in molecular neuroscience

    2023  Band 16, Seite(n) 1215637

    Abstract: Introduction: Vascular dementia (VaD) is one of the most common causes of dementia among the elderly. Despite this, the molecular basis of VaD remains poorly characterized when compared to other age-related dementias. Pervasive cerebral elevations of ... ...

    Abstract Introduction: Vascular dementia (VaD) is one of the most common causes of dementia among the elderly. Despite this, the molecular basis of VaD remains poorly characterized when compared to other age-related dementias. Pervasive cerebral elevations of urea have recently been reported in several dementias; however, a similar analysis was not yet available for VaD.
    Methods: Here, we utilized ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to measure urea levels from seven brain regions in post-mortem tissue from cases of VaD (
    Results: Elevated urea levels ranging from 2.2- to 2.4-fold-change in VaD cases were identified in six out of the seven regions analysed, which are similar in magnitude to those observed in uremic encephalopathy. Fold-elevation of urea was highest in the basal ganglia and hippocampus (2.4-fold-change), consistent with the observation that these regions are severely affected in VaD.
    Discussion: Taken together, these data not only describe a multiregional elevation of brain-urea levels in VaD but also imply the existence of a common urea-mediated disease mechanism that is now known to be present in at least four of the main age-related dementias.
    Sprache Englisch
    Erscheinungsdatum 2023-07-13
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2023.1215637
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Widespread severe cerebral elevations of haptoglobin and haemopexin in sporadic Alzheimer's disease: Evidence for a pervasive microvasculopathy.

    Philbert, Sasha A / Xu, Jingshu / Unwin, Richard D / Dowsey, Andrew W / Cooper, Garth J S

    Biochemical and biophysical research communications

    2021  Band 555, Seite(n) 89–94

    Abstract: Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure ... ...

    Abstract Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration but there are no available treatments with demonstrated disease-modifying actions. It is therefore relevant to study hitherto-unknown aspects of brain structure and function to seek new disease-related mechanisms that might be targeted by novel disease-modifying interventions. During hypothesis-generating proteomic investigations in a case-control study of sAD, we observed widespread elevations of haptoglobin and haemopexin in all six brain-regions studied, which together represent much of the brain. Measured perturbations were significant, with the posterior probability of upregulation generally >95% and haptoglobin doubling in expression levels on average across deep brain structures (hippocampus, entorhinal cortex and cingulate gyrus) as well as sensory and motor cortices, and cerebellum. Haptoglobin and haemopexin are often regarded as circulating proteins whose main functions are to bind, respectively, the strongly pro-inflammatory extracellular haemoglobin and haeme molecules that form following haemolysis, thereby promoting their clearance and suppressing damage they might otherwise cause, for example, acute kidney injury. To our knowledge, elevations in neither cerebral haptoglobin nor haemopexin have previously been linked to the pathogenesis of sAD. Post-mortem examination of these cases showed no signs of macroscopic cerebral haemorrhage. These findings demonstrate pervasive cerebral elevation of haptoglobin and haemopexin, consistent with low-level intracerebral leakage of haemoglobin and consequent haeme formation throughout sAD brain. They point to a widespread underlying microvasculopathy that facilitates erythrocyte leakage, thereby triggering elevated tissue-free haemoglobin and driving the measured elevations in haptoglobin and haemopexin.
    Mesh-Begriff(e) Aged ; Alzheimer Disease/metabolism ; Blood-Brain Barrier/physiopathology ; Brain/blood supply ; Brain/metabolism ; Brain/physiopathology ; Case-Control Studies ; Cerebrovascular Disorders/metabolism ; Cerebrovascular Disorders/physiopathology ; Female ; Haptoglobins/analysis ; Hemopexin/analysis ; Humans ; Iron/analysis ; Iron/metabolism ; Male
    Chemische Substanzen Haptoglobins ; Hemopexin (9013-71-2) ; Iron (E1UOL152H7)
    Sprache Englisch
    Erscheinungsdatum 2021-04-01
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2021.02.107
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 116: Hefte anzeigen Standort:
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  3. Artikel ; Online: Elevated hippocampal copper in cases of type 2 diabetes.

    Philbert, Sasha A / Schönberger, Sarah J / Xu, Jingshu / Church, Stephanie J / Unwin, Richard D / Cooper, Garth J S

    EBioMedicine

    2022  Band 86, Seite(n) 104317

    Abstract: Background: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease ( ...

    Abstract Background: Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaired cerebral-glucose uptake, elevation of cerebral glucose but not blood glucose levels, and widespread cerebral-copper deficiency. We hypothesized that sAD-like brain-metal perturbations would occur in T2D.
    Methods: We measured nine essential elements in an observational case-control study of T2D without dementia (6 cases and 6 controls) in four brain regions and compared the results with those from our study of brain metals in sAD (9 cases and 9 controls), which employed equivalent analytical methodology. We evaluated intergroup differences by supervised and unsupervised multivariate-statistical approaches to contrast between T2D cases and controls, and to compare them with cerebral-metal patterns in sAD.
    Findings: Unexpectedly, we found that hippocampal-copper levels in T2D were markedly elevated compared with controls (P = 0.005 and 0.007 by Welch's t-test in two technical-replicate experiments), to levels similar to those in cases of untreated Wilson's disease (WD), wherein elevated cerebral copper causes neurodegeneration. By contrast, hippocampal-copper levels in sAD were markedly deficient. Multivariate analysis identified marked differences in patterns of essential metals between hippocampal datasets from cases of T2D and of sAD.
    Interpretation: Elevated hippocampal copper could contribute to the pathogenesis of cerebral neurodegeneration and cognitive impairment in T2D, similar to known impacts of elevated brain copper in WD. Therapeutic approaches with copper-lowering agents similar to those currently employed in pharmacotherapy of WD, may also be applicable in patients with T2D and impaired cognitive function. Further studies will be required to replicate and extend these findings and to investigate their potential therapeutic implications.
    Funding: In Acknowledgments, includes Endocore Research Trust; Lee Trust; Oakley Mental Health Research Foundation; Ministry of Business, Innovation & Employment; The Universities of Auckland and Manchester, and others.
    Sprache Englisch
    Erscheinungsdatum 2022-11-03
    Erscheinungsland Netherlands
    Dokumenttyp Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2022.104317
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Pan-cerebral sodium elevations in vascular dementia: Evidence for disturbed brain-sodium homeostasis.

    Philbert, Sasha A / Xu, Jingshu / Church, Stephanie J / Unwin, Richard D / Roncaroli, Federico / Cooper, Garth J S

    Frontiers in aging neuroscience

    2022  Band 14, Seite(n) 926463

    Abstract: Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite ... ...

    Abstract Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in
    Sprache Englisch
    Erscheinungsdatum 2022-07-18
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2022.926463
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Contrasting Sodium and Potassium Perturbations in the Hippocampus Indicate Potential Na

    Philbert, Sasha A / Xu, Jingshu / Scholefield, Melissa / Church, Stephanie J / Unwin, Richard D / Cooper, Garth J S

    Frontiers in aging neuroscience

    2022  Band 14, Seite(n) 822787

    Abstract: Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the ... ...

    Abstract Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal
    Sprache Englisch
    Erscheinungsdatum 2022-01-28
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2022.822787
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimer's Disease Consistent With Cerebral Pantothenate Deficiency.

    Sang, Crystal / Philbert, Sasha A / Hartland, Danielle / Unwin, Richard D / Dowsey, Andrew W / Xu, Jingshu / Cooper, Garth J S

    Frontiers in aging neuroscience

    2022  Band 14, Seite(n) 893159

    Abstract: Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably ... ...

    Abstract Sporadic Alzheimer's disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes.
    Sprache Englisch
    Erscheinungsdatum 2022-06-10
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article
    ZDB-ID 2558898-9
    ISSN 1663-4365
    ISSN 1663-4365
    DOI 10.3389/fnagi.2022.893159
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel: Full-length ATP7B reconstituted through protein

    Padula, Agnese / Petruzzelli, Raffaella / Philbert, Sasha A / Church, Stephanie J / Esposito, Federica / Campione, Severo / Monti, Marcello / Capolongo, Filomena / Perna, Claudia / Nusco, Edoardo / Schmidt, Hartmut H / Auricchio, Alberto / Cooper, Garth J S / Polishchuk, Roman / Piccolo, Pasquale

    Molecular therapy. Methods & clinical development

    2022  Band 26, Seite(n) 495–504

    Abstract: Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length ... ...

    Abstract Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length human
    Sprache Englisch
    Erscheinungsdatum 2022-08-13
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2872938-9
    ISSN 2329-0501 ; 2329-0501
    ISSN (online) 2329-0501
    ISSN 2329-0501
    DOI 10.1016/j.omtm.2022.08.004
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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 7107: Hefte anzeigen Standort:
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