Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableMetals and Alzheimer's disease(IOS PRESS, 2006-11)There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta. As such, a dysregulation of metal ion homeostasis, as occurs with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions.
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ItemMetal chaperones: a holistic approach to the treatment of Alzheimer's disease.(Frontiers Media, 2012-03-02)As evidence for the role of metal ion dysregulation in the pathogenesis of multiple CNS disorders grows, it has become important to more precisely identify and differentiate the biological effects of various pharmacological modulators of metal ion homeostasis. This is particularly evident in disorders such as Alzheimer's disease (AD), where the use of metal chaperones (that transport metals), as opposed to chelators (which exclude metals from biological interactions), may prove to be the first truly disease modifying approach for this condition. The purpose of this mini-review is to highlight the emerging notion that metal chaperones, such as PBT2 (Prana Biotechnology), modulate a variety of critical pathways affecting key aspects of the AD cascade to provide a more "holistic" approach to the treatment of this disease.
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ItemCopper modulation as a therapy for Alzheimer's disease?(Hindawi Limited, 2011)The role of metals in the pathophysiology of Alzheimer's disease (AD) has gained considerable support in recent years, with both in vitro and in vivo data demonstrating that a mis-metabolism of metal ions, such as copper and zinc, may affect various cellular cascades that ultimately leads to the development and/or potentiation of AD. In this paper, we will provide an overview of the preclinical and clinical literature that specifically relates to attempts to affect the AD cascade by the modulation of brain copper levels. We will also detail our own novel animal data, where we treated APP/PS1 (7-8 months old) mice with either high copper (20 ppm in the drinking water), high cholesterol (2% supplement in the food) or a combination of both and then assessed β-amyloid (Aβ) burden (soluble and insoluble Aβ), APP levels and behavioural performance in the Morris water maze. These data support an interaction between copper/cholesterol and both Aβ and APP and further highlight the potential role of metal ion dyshomeostasis in AD.
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ItemNo Preview AvailableA comparison of ceruloplasmin to biological polyanions in promoting the oxidation of Fe2+ under physiologically relevant conditions(ELSEVIER SCIENCE BV, 2014-12)BACKGROUND: Iron oxidation is thought to be predominantly handled enzymatically in the body, to minimize spontaneous combustion with oxygen and to facilitate cellular iron export by loading transferrin. This process may be impaired in disease, and requires more accurate analytical assays to interrogate enzymatic- and auto-oxidation within a physiologically relevant environment. METHOD: A new triplex ferroxidase activity assay has been developed that overcomes the previous assay limitations of measuring iron oxidation at a physiologically relevant pH and salinity. RESULTS: Revised enzymatic kinetics for ceruloplasmin (Vmax≈35μMFe(3+)/min/μM; Km≈15μM) are provided under physiological conditions, and inhibition by sodium azide (Ki for Ferric Gain 78.3μM, Ki for transferrin loading 8.1×10(4)μM) is quantified. We also used this assay to characterize the non-enzymatic oxidation of iron that proceeded linearly under physiological conditions. CONCLUSIONS AND GENERAL SIGNIFICANCE: These findings indicate that the requirement of an enzyme to oxidize iron may only be necessary under conditions of adverse pH or anionic strength, for example from hypoxia. In a normal physiological environment, Fe(3+) incorporation into transferrin would be sufficiently enabled by the biological polyanions that are prevalent within extracellular fluids.
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ItemThe effect of paraformaldehyde fixation and sucrose cryoprotection on metal concentration in murine neurological tissue(ROYAL SOC CHEMISTRY, 2014-03)
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ItemCharacterization of the role of the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer's disease(SPRINGER BASEL AG, 2012-11)Alzheimer's disease (AD) is by far the most commonly diagnosed dementia, and despite multiple efforts, there are still no effective drugs available for its treatment. One strategy that deserves to be pursued is to alter the expression and/or physiological action of endogenous proteins instead of administering exogenous factors. In this study, we intend to characterize the roles of the antioxidant, anti-inflammatory, and heavy-metal binding proteins, metallothionein-1 + 2 (MT1 + 2), in a mouse model of Alzheimer's disease, Tg2576 mice. Contrary to expectations, MT1 + 2-deficiency rescued partially the human amyloid precursor protein-induced changes in mortality and body weight in a gender-dependent manner. On the other hand, amyloid plaque burden was decreased in the cortex and hippocampus in both sexes, while the amyloid cascade, neuroinflammation, and behavior were affected in the absence of MT1 + 2 in a complex manner. These results highlight that the control of the endogenous production and/or action of MT1 + 2 could represent a powerful therapeutic target in AD.
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ItemCharacterization of the role of metallothionein-3 in an animal model of Alzheimer's disease(SPRINGER BASEL AG, 2012-11)Among the dementias, Alzheimer's disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn(7)MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.
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ItemPharmacotherapeutic targets in Alzheimer's disease(WILEY, 2009-01)Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.
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ItemIron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease(BMC, 2014-07-10)BACKGROUND: The substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson's disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice. FINDINGS: We show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9-14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs. CONCLUSIONS: We conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson's disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options.
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ItemA review of β-amyloid neuroimaging in Alzheimer's disease(Frontiers Research Foundation, 2014)Alzheimer's disease (AD) is the most common cause of dementia worldwide. As advancing age is the greatest risk factor for developing AD, the number of those afflicted is expected to increase markedly with the aging of the world's population. The inability to definitively diagnose AD until autopsy remains an impediment to establishing effective targeted treatments. Neuroimaging has enabled in vivo visualization of pathological changes in the brain associated with the disease, providing a greater understanding of its pathophysiological development and progression. However, neuroimaging biomarkers do not yet offer clear advantages over current clinical diagnostic criteria for them to be accepted into routine clinical use. Nonetheless, current insights from neuroimaging combined with the elucidation of biochemical and molecular processes in AD are informing the ongoing development of new imaging techniques and their application. Much of this research has been greatly assisted by the availability of transgenic mouse models of AD. In this review we summarize the main efforts of neuroimaging in AD in humans and in mouse models, with a specific focus on ß-amyloid, and discuss the potential of new applications and novel approaches.