Florey Department of Neuroscience and Mental Health - Research Publications
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ItemL-3,4-dihydroxyphenylalanine (L-DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson's disease(WILEY, 2019-07)Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that l-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized motor performance, when excess Fe was present. Similarly, l-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.
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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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ItemThe Down Syndrome-Associated Protein, Regulator of Calcineurin-1, is Altered in Alzheimer's Disease and Dementia with Lewy Bodies(OMICS International, 2019)There is a known relationship between Alzheimer's disease (AD) and Down syndrome (DS), with the latter typically developing AD-like neuropathology in mid-life. In order to further understand this relationship we examined intersectin-1 (ITSN1) and the regulator of calcineurin-1 (RCAN1), proteins involved in endosomal and lysosomal trafficking that are over-expressed in DS. We examined RCAN1 and ITSN1 levels (both long (-L) and short (-S) isoforms) and the level of endogenous metals in White Blood Cells (WBCs) collected from AD patients who were enrolled in the Australian Imaging, Biomarker and Lifestyle Study on Ageing (AIBL). We also examined RCAN1 and ITSN1-S and -L in post-mortem brain tissue in a separate cohort of patients with AD or other types of dementia including Dementia with Lewy Bodies (DLB) and non-Alzheimer's disease dementia. We found that RCAN1 was significantly elevated in AD and DLB brain compared with controls, but there was no difference in the level of RCAN1 in WBCs of AD patients. There were no differences in the levels of ITSN1-L and -S between AD and the control, nor between other types of dementia and the control. We found that there were no differences in the levels of metals between AD and the control WBCs. In conclusion, our data demonstrate that RCAN1 is differentially regulated between the peripheral and central compartments in AD and should be further investigated to understand its potential role in dementia of AD and DLB.
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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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ItemZn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?(MDPI, 2019-01)Acrodermatitis enteropathica (AE) is a rare disease characterised by a failure in intestinal zinc absorption, which results in a host of symptoms that can ultimately lead to death if left untreated. Current clinical treatment involves life-long high-dose zinc supplements, which can introduce complications for overall nutrient balance in the body. Previous studies have therefore explored the pharmacological treatment of AE utilising metal ionophore/transport compounds in an animal model of the disease (conditional knockout (KO) of the zinc transporter, Zip4), with the perspective of finding an alternative to zinc supplementation. In this study we have assessed the utility of a different class of zinc ionophore compound (zinc diethyl bis(N4-methylthiosemicarbazone), Zn-DTSM; Collaborative Medicinal Development, Sausalito, CA, USA) to the one we have previously described (clioquinol), to determine whether it is effective at preventing the stereotypical weight loss present in the animal model of disease. We first utilised an in vitro assay to assess the ionophore capacity of the compound, and then assessed the effect of the compound in three in vivo animal studies (in 1.5-month-old mice at 30 mg/kg/day, and in 5-month old mice at 3 mg/kg/day and 30 mg/kg/day). Our data demonstrate that Zn-DTSM has a pronounced effect on preventing weight loss when administered daily at 30 mg/kg/day; this was apparent in the absence of any added exogenous zinc. This compound had little overall effect on zinc content in various tissues that were assessed, although further characterisation is required to more fully explore the cellular changes underlying the physiological benefit of this compound. These data suggest that Zn-DTSM, or similar compounds, should be further explored as potential therapeutic options for the long-term treatment of AE.
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ItemIn vivo synaptic activity-independent co-uptakes of amyloid β1-42 and Zn2+ into dentate granule cells in the normal brain(NATURE PORTFOLIO, 2019-04-24)Neuronal amyloid β1-42 (Aβ1-42) accumulation is considered an upstream event in Alzheimer's disease pathogenesis. Here we report the mechanism on synaptic activity-independent Aβ1-42 uptake in vivo. When Aβ1-42 uptake was compared in hippocampal slices after incubating with Aβ1-42, In vitro Aβ1-42 uptake was preferentially high in the dentate granule cell layer in the hippocampus. Because the rapid uptake of Aβ1-42 with extracellular Zn2+ is essential for Aβ1-42-induced cognitive decline in vivo, the uptake mechanism was tested in dentate granule cells in association with synaptic activity. In vivo rapid uptake of Aβ1-42 was not modified in the dentate granule cell layer after co-injection of Aβ1-42 and tetrodotoxin, a Na+ channel blocker, into the dentate gyrus. Both the rapid uptake of Aβ1-42 and Zn2+ into the dentate granule cell layer was not modified after co-injection of CNQX, an AMPA receptor antagonist, which blocks extracellular Zn2+ influx, Both the rapid uptake of Aβ1-42 and Zn2+ into the dentate granule cell layer was not also modified after either co-injection of chlorpromazine or genistein, an endocytic repressor. The present study suggests that Aβ1-42 and Zn2+ are synaptic activity-independently co-taken up into dentate granule cells in the normal brain and the co-uptake is preferential in dentate granule cells in the hippocampus. We propose a hypothesis that Zn-Aβ1-42 oligomers formed in the extracellular compartment are directly incorporated into neuronal plasma membranes and form Zn2+-permeable ion channels.
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ItemExtracellular Zn2+ Is Essential for Amyloid β1-42-Induced Cognitive Decline in the Normal Brain and Its Rescue(SOC NEUROSCIENCE, 2017-07-26)Brain Aβ1-42 accumulation is considered an upstream event in pathogenesis of Alzheimer's disease. However, accumulating evidence indicates that other neurochemical changes potentiate the toxicity of this constitutively generated peptide. Here we report that the interaction of Aβ1-42 with extracellular Zn2+ is essential for in vivo rapid uptake of Aβ1-42 and Zn2+ into dentate granule cells in the normal rat hippocampus. The uptake of both Aβ1-42 and Zn2+ was blocked by CaEDTA, an extracellular Zn2+ chelator, and by Cd2+, a metal that displaces Zn2+ for Aβ1-42 binding. In vivo perforant pathway LTP was unaffected by perfusion with 1000 nm Aβ1-42 in ACSF without Zn2+ However, LTP was attenuated under preperfusion with 5 nm Aβ1-42 in ACSF containing 10 nm Zn2+, recapitulating the concentration of extracellular Zn2+, but not with 5 nm Aβ1-40 in ACSF containing 10 nm Zn2+ Aβ1-40 and Zn2+ were not taken up into dentate granule cells under these conditions, consistent with lower affinity of Aβ1-40 for Zn2+ than Aβ1-42 Aβ1-42-induced attenuation of LTP was rescued by both CaEDTA and CdCl2, and was observed even with 500 pm Aβ1-42 Aβ1-42 injected into the dentate granule cell layer of rats induced a rapid memory disturbance that was also rescued by coinjection of CdCl2 The present study supports blocking the formation of Zn-Aβ1-42 in the extracellular compartment as an effective preventive strategy for Alzheimer's disease.SIGNIFICANCE STATEMENT Short-term memory loss occurs in normal elderly and increases in the predementia stage of Alzheimer's disease (AD). Amyloid-β1-42 (Aβ1-42), a possible causing peptide in AD, is bound to Zn2+ in the extracellular compartment in the hippocampus induced short-term memory loss in the normal rat brain, suggesting that extracellular Zn2+ is essential for Aβ1-42-induced short-term memory loss. The evidence is important to find an effective preventive strategy for AD, which is blocking the formation of Zn-Aβ1-42 in the extracellular compartment.
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ItemTau-mediated iron export prevents ferroptotic damage after ischemic stroke(NATURE PUBLISHING GROUP, 2017-11)Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.
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ItemMetals and Alzheimer's Disease: How Far Have We Come in the Clinic?(IOS PRESS, 2018)It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer's disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD.
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ItemVisualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging (vol 6, pg 5383, 2015)(ROYAL SOC CHEMISTRY, 2016)[This corrects the article DOI: 10.1039/C5SC02231B.].