Florey Department of Neuroscience and Mental Health - Research Publications
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ItemAltered amyloid precursor protein, tau-regulatory proteins, neuronal numbers and behaviour, but no tau pathology, synaptic and inflammatory changes or memory deficits, at 1 month following repetitive mild traumatic brain injury(WILEY, 2022-11)Repetitive mild traumatic brain injury, commonly experienced following sports injuries, results in various secondary injury processes and is increasingly recognised as a risk factor for the development of neurodegenerative conditions such as chronic traumatic encephalopathy, which is characterised by tau pathology. We aimed to characterise the underlying pathological mechanisms that might contribute to the onset of neurodegeneration and behavioural changes in the less-explored subacute (1-month) period following single or repetitive controlled cortical impact injury (five impacts, 48 h apart) in 12-week-old male and female C57Bl6 mice. We conducted motor and cognitive testing, extensively characterised the status of tau and its regulatory proteins via western blot and quantified neuronal populations using stereology. We report that r-mTBI resulted in neurobehavioural deficits, gait impairments and anxiety-like behaviour at 1 month post-injury, effects not seen following a single injury. R-mTBI caused a significant increase in amyloid precursor protein, an increased trend towards tau phosphorylation and significant changes in kinase/phosphatase proteins that may promote a downstream increase in tau phosphorylation, but no changes in synaptic or neuroinflammatory markers. Lastly, we report neuronal loss in various brain regions following both single and repeat injuries. We demonstrate herein that repeated impacts are required to promote the initiation of a cascade of biochemical events that are consistent with the onset of neurodegeneration subacutely post-injury. Identifying the timeframe in which these changes occur and the pathological mechanisms involved will be crucial for the development of future therapeutics to prevent the onset or mitigate the progression of neurodegeneration following r-mTBI.
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ItemATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism(SPRINGER, 2022-10)Hyposmia is a prevalent prodromal feature of Parkinson's disease (PD), though the neuropathology that underlies this symptom is poorly understood. Unlike the substantia nigra, the status of metal homeostasis in the olfactory bulbs has not been characterized in PD. Given the increasing interest in metal modulation as a therapeutic avenue in PD, we sought to investigate bulbar metals and the effect of AT434 (formerly PBT434) an orally bioavailable, small molecule modulator of metal homeostasis on hyposmia in a mouse model of parkinsonism (the tau knockout (tau-/-) mouse). 5.5 (pre-hyposmia) and 13.5-month-old (pre-motor) mice were dosed with ATH434 (30 mg/kg/day, oral gavage) for 6 weeks. Animals then underwent behavioral analysis for olfactory and motor phenotypes. The olfactory bulbs and the substantia nigra were then collected and analyzed for metal content, synaptic markers, and dopaminergic cell number. ATH434 was able to prevent the development of hyposmia in young tau-/- mice, which coincided with a reduction in bulbar iron and copper levels, an increase in synaptophysin, and a reduction in soluble α-synuclein. ATH434 was able to prevent the development of motor impairment in aged tau-/- mice, which coincided with a reduction in iron levels and reduced neurodegeneration in the substantia nigra. These data implicate metal dyshomeostasis in parkinsonian olfactory deficits, and champion a potential clinical benefit of ATH434 in both prodromal and clinical stages of PD.
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ItemThe Compound ATH434 Prevents Alpha-Synuclein Toxicity in a Murine Model of Multiple System Atrophy(IOS PRESS, 2022)BACKGROUND: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson's disease and shown that it is brain-penetrant, reduces iron accumulation and iron-mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. OBJECTIVE: To evaluate the efficacy of ATH434 in a mouse MSA model. METHODS: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. RESULTS: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric "species of synuclein". CONCLUSION: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA.
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ItemATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson's Disease(IOS PRESS, 2021)BACKGROUND: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. OBJECTIVE: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. METHODS: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group"). RESULTS: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. CONCLUSION: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.
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ItemEvaluation of attention in APP/PS1 mice shows impulsive and compulsive behaviours(WILEY, 2021-01)While Alzheimer's disease (AD) is traditionally associated with deficits in episodic memory, early changes in other cognitive domains, such as attention, have been gaining interest. In line with clinical observations, some animal models of AD have been shown to develop attentional deficits, but this is not consistent across all models. The APPswe/PS1ΔE9 (APP/PS1) mouse is one of the most commonly used AD models and attention has not yet been scrutinised in this model. We set out to assess attention using the 5-choice serial reaction time task (5CSRTT) early in the progression of cognitive symptoms in APP/PS1 mice, using clinically translatable touchscreen chambers. APP/PS1 mice showed no attentional changes across 5CSRTT training or any probes from 9 to 11 months of age. Interestingly, APP/PS1 mice showed increased impulsive and compulsive responding when task difficulty was high. This suggests that while the APP/PS1 mouse model may not be a good model of attentional changes in AD, it may be useful to study the early changes in impulsive and compulsive behaviour that have been identified in patient studies. As these changes have not previously been reported without attentional deficits in the clinic, the APP/PS1 mouse model may provide a unique opportunity to study these specific behavioural changes seen in AD, including their mechanistic underpinnings and therapeutic implications.
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ItemThe Long Isoform of Intersectin-1 Has a Role in Learning and Memory(FRONTIERS MEDIA SA, 2020-02-25)Down syndrome is caused by partial or total trisomy of chromosome 21 and is characterized by intellectual disability and other disorders. Although it is difficult to determine which of the genes over-expressed on the supernumerary chromosome contribute to a specific abnormality, one approach is to study each gene in isolation. This can be accomplished either by using an over-expression model to study increased gene dosage or a gene-deficiency model to study the biological function of the gene. Here, we extend our examination of the function of the chromosome 21 gene, ITSN1. We used mice in which the long isoform of intersectin-1 was knocked out (ITSN1-LKO) to understand how a lack of the long isoform of ITSN1 affects brain function. We examined cognitive and locomotor behavior as well as long term potentiation (LTP) and the mitogen-activated protein kinase (MAPK) and 3'-kinase-C2β-AKT (AKT) cell signaling pathways. We also examined the density of dendritic spines on hippocampal pyramidal neurons. We observed that ITSN1-LKO mice had deficits in learning and long term spatial memory. They also exhibited impaired LTP, and no changes in the levels of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2. The amount of phosphorylated AKT was reduced in the ITSN1-LKO hippocampus and there was a decrease in the number of apical dendritic spines in hippocampal neurons. Our data suggest that the long isoform of ITSN1 plays a part in normal learning and memory.
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ItemZinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome(MDPI, 2020-02)Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer's disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals. To do this, we utilised size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) and examined hippocampal homogenates from ZnT3 KO and age-matched wild-type mice at 3, 6 and 18 months of age. Our data suggest that there are alterations in specific metal binding proteins, for zinc, copper and iron all being modulated in the ZnT3 KO mice compared to wild-type (WT). These data suggest that ZnT3 KO mice may have impairments in the levels or localisation of multiple transition metals, and that copper- and iron-dependent cellular pathways may also be impacted in these mice.
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ItemBrain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington's Disease.(Springer Nature, 2020-01)There is currently no disease-modifying treatment for Huntington's disease (HD), which is characterized by chorea motor impairment and cognitive decline. The zinc ionophore, PBT2, was previously shown to improve the phenotype of a HD mouse model and reported efficacy in certain cognitive tests in a phase II clinical trial in HD. Here we report that zinc deficiency is a feature of the hippocampus and cortex in the R6/1 mouse model of HD. Low cortical zinc has been shown to induce cognitive impairment, and indeed, dietary restriction of zinc in R6/1 mice was associated with cognitive impairment in the Y-maze, an exacerbated hippocampal long-term potentiation (LTP) deficit and reduction of AMPA receptors (and not other glutamatergic receptors). These data reveal the importance of zinc in maintaining brain function in HD.