Florey Department of Neuroscience and Mental Health - Research Publications

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    Paradoxical effects of exercise on hippocampal plasticity and cognition in mice with a heterozygous null mutation in the serotonin transporter gene
    Rogers, J ; Chen, F ; Stanic, D ; Farzana, F ; Li, S ; Zeleznikow-Johnston, AM ; Nithianantharajah, J ; Churilov, IL ; Adlard, PA ; Lanfumey, L ; Hannan, AJ ; Renoir, T (WILEY, 2019-09)
    BACKGROUND AND PURPOSE: Exercise is known to improve cognitive function, but the exact synaptic and cellular mechanisms remain unclear. We investigated the potential role of the serotonin (5-HT) transporter (SERT) in mediating these effects. EXPERIMENTAL APPROACH: Hippocampal long-term potentiation (LTP) and neurogenesis were measured in standard-housed and exercising (wheel running) wild-type (WT) and SERT heterozygous (HET) mice. We also assessed hippocampal-dependent cognition using the Morris water maze (MWM) and a spatial pattern separation touchscreen task. KEY RESULTS: SERT HET mice had impaired hippocampal LTP regardless of the housing conditions. Exercise increased hippocampal neurogenesis in WT mice. However, this was not observed in SERT HET animals, even though both genotypes used the running wheels to a similar extent. We also found that standard-housed SERT HET mice displayed altered cognitive flexibility than WT littermate controls in the MWM reversal learning task. However, SERT HET mice no longer exhibited this phenotype after exercise. Cognitive changes, specific to SERT HET mice in the exercise condition, were also revealed on the touchscreen spatial pattern separation task, especially when the cognitive pattern separation load was at its highest. CONCLUSIONS AND IMPLICATIONS: Our study is the first evidence of reduced hippocampal LTP in SERT HET mice. We also show that functional SERT is required for exercise-induced increase in adult neurogenesis. Paradoxically, exercise had a negative impact on hippocampal-dependent cognitive tasks, especially in SERT HET mice. Taken together, our results suggest unique complex interactions between exercise and altered 5-HT homeostasis.
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    L-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
    Billings, JL ; Gordon, SL ; Rawling, T ; Doble, PA ; Bush, AI ; Adlard, PA ; Finkelstein, DI ; Hare, DJ (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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    Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc
    Foliaki, ST ; Lewis, V ; Islam, AMT ; Ellett, LJ ; Senesi, M ; Finkelstein, DI ; Roberts, B ; Lawson, VA ; Adlard, PA ; Collins, SJ ; Westaway, D (PUBLIC LIBRARY SCIENCE, 2019-04)
    Although considerable evidence supports that misfolded prion protein (PrPSc) is the principal component of "prions", underpinning both transmissibility and neurotoxicity, clear consensus around a number of fundamental aspects of pathogenesis has not been achieved, including the time of appearance of neurotoxic species during disease evolution. Utilizing a recently reported electrophysiology paradigm, we assessed the acute synaptotoxicity of ex vivo PrPSc prepared as crude homogenates from brains of M1000 infected wild-type mice (cM1000) harvested at time-points representing 30%, 50%, 70% and 100% of the terminal stage of disease (TSD). Acute synaptotoxicity was assessed by measuring the capacity of cM1000 to impair hippocampal CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in explant slices. Of particular note, cM1000 from 30% of the TSD was able to cause significant impairment of LTP and PTP, with the induced failure of LTP increasing over subsequent time-points while the capacity of cM1000 to induce PTP failure appeared maximal even at this early stage of disease progression. Evidence that the synaptotoxicity directly related to PrP species was demonstrated by the significant rescue of LTP dysfunction at each time-point through immuno-depletion of >50% of total PrP species from cM1000 preparations. Moreover, similar to our previous observations at the terminal stage of M1000 prion disease, size fractionation chromatography revealed that capacity for acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, with the profile appearing maximised by 50% of the TSD. Using enhanced sensitivity western blotting, modestly proteinase K (PK)-resistant PrPSc was detectable at very low levels in cM1000 at 30% of the TSD, becoming robustly detectable by 70% of the TSD at which time substantial levels of highly PK-resistant PrPSc was also evident. Further illustrating the biochemical evolution of acutely synaptotoxic species the synaptotoxicity of cM1000 from 30%, 50% and 70% of the TSD, but not at 100% TSD, was abolished by digestion of immuno-captured PrP species with mild PK treatment (5μg/ml for an hour at 37°C), demonstrating that the predominant synaptotoxic PrPSc species up to and including 70% of the TSD were proteinase-sensitive. Overall, these findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, albeit with eventual plateauing of transmitting conformers.
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    Iron is increased in the brains of ageing mice lacking the neurofilament light gene
    Vickers, JC ; King, AE ; McCormack, GH ; Bindoff, AD ; Adlard, PA ; Ginsberg, SD (PUBLIC LIBRARY SCIENCE, 2019-10-23)
    There has been strong interest in the role of metals in neurodegeneration, and how ageing may predispose the brain to related diseases such as Alzheimer's disease. Recent work has also highlighted a potential interaction between different metal species and various components of the cytoskeletal network in the brain, which themselves have a reported role in age-related degenerative disease and other neurological disorders. Neurofilaments are one such class of intermediate filament protein that have a demonstrated capacity to bind and utilise cation species. In this study, we investigated the consequences of altering the neurofilamentous network on metal ion homeostasis by examining neurofilament light (NFL) gene knockout mice, relative to wildtype control animals, at adulthood (5 months of age) and advanced age (22 months). Inductively coupled plasma mass spectroscopy demonstrated that the concentrations of iron (Fe), copper (Cu) and zinc (Zn) varied across brain regions and peripheral nerve samples. Zn and Fe showed statistically significant interactions between genotype and age, as well as between genotype and region, and Cu demonstrated a genotype and region interaction. The most substantial difference between genotypes was found in Fe in the older animals, where, across many regions examined, there was elevated Fe in the NFL knockout mice. This data indicates a potential relationship between the neurofilamentous cytoskeleton and the processing and/or storage of Fe through ageing.
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    The Down Syndrome-Associated Protein, Regulator of Calcineurin-1, is Altered in Alzheimer's Disease and Dementia with Lewy Bodies
    Malakooti, N ; FOWLER, C ; Volitakis, I ; McLean, CA ; Kim, RC ; Bush, A ; REMBACH, A ; PRITCHARD, MA ; Finkelstein, DI ; Adlard, PA (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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    Zn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?
    Bray, L ; Volitakis, I ; Ayton, S ; Bush, AI ; Adlard, PA (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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    In vivo synaptic activity-independent co-uptakes of amyloid β1-42 and Zn2+ into dentate granule cells in the normal brain
    Tamano, H ; Oneta, N ; Shioya, A ; Adlard, PA ; Bush, A ; Takeda, A (NATURE PUBLISHING GROUP, 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.