Florey Department of Neuroscience and Mental Health - Research Publications
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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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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 novel approach to rapidly prevent age-related cognitive decline(WILEY, 2014-04)The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.
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ItemMitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau(PUBLIC LIBRARY SCIENCE, 2007-06-20)Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.
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ItemThe effect of dopamine on MPTP-induced rotarod disability(ELSEVIER IRELAND LTD, 2013-05-24)UNLABELLED: Dopamine depletion in Parkinson's disease (PD) results in bradykinesia and tremor. Therapeutic administration of the dopamine precursor, l-Dopa, alleviates these symptoms but dyskinesia's can manifest with chronic treatment. In the MPTP toxin mouse model of PD, lesion severity is often assessed by the rotarod behavioral assay. Dopamine depletion by MPTP is thought to induce rotarod behavioral decline. Here we surveyed rotarod behavior and striatal dopamine at timed intervals post-MPTP. Paradoxically, rotarod disability coincided with gradual striatal dopamine restoration. l-Dopa supplementation exacerbated rotarod disability, whereas dopamine antagonism restored performance. CONCLUSION: dopamine restoration, not depletion, precipitates rotarod disability after MPTP intoxication, and caution should be applied when using this assay for MPTP.