The Mental Health Research Institute
The Mental Health Research Institute
Camfield D.A.,Swinburne University of Technology |
Sarris J.,Swinburne University of Technology |
Sarris J.,University of Melbourne |
Berk M.,University of Melbourne |
And 3 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2011
Obsessive-Compulsive Disorder (OCD) is a debilitating mental illness which has a significant impact on quality of life. First-line SSRI treatments for OCD typically are of limited benefit to only 40-60% of patients, and are associated with a range of adverse side effects. Current preclinical research investigating nutraceuticals (natural products) for OCD, reveals encouraging novel activity in modulating key pathways suggested to be involved in the pathogenesis of OCD (glutamatergic and serotonergic pathway dysregulation). Emerging clinical evidence also appears to tentatively support certain nutrients and plant-based interventions with known active constituents which modulate these pathways: N-acetlycysteine, myo-inositol, glycine, and milk thistle (Silybum marianum). The serotonin precursor tryptophan is unlikely to be of use in treating OCD while 5-HTP may possibly be a more effective precursor strategy. However, there is currently no clinical evidence to test the efficacy of either of these substances. Currently the balance of clinical evidence does not support the use of St. John's wort (Hypericum perforatum) in OCD. While clinical research in this area is in its infancy, further research into nutraceuticals is warranted in light of the promising preclinical data regarding their mechanisms of action and their favourable side effect profiles in comparison to current SSRI treatments. It is recommended that future clinical trials of nutraceutical treatments for OCD utilize randomized placebo-controlled study designs and considerably larger sample sizes in order to properly test for efficacy. © 2011 Elsevier Inc.
Sensi S.L.,University of Chieti Pescara |
Sensi S.L.,University of California at Irvine |
Paoletti P.,French Institute of Health and Medical Research |
Koh J.-Y.,University of Ulsan |
And 5 more authors.
Journal of Neuroscience | Year: 2011
Our understanding of the roles played by zinc in the physiological and pathological functioning of the brain is rapidly expanding. The increased availability of genetically modified animal models, selective zinc-sensitive fluorescent probes, and novel chelators is producing a remarkable body of exciting new data that clearly establishes this metal ion as a key modulator of intracellular and intercellular neuronal signaling. In this Mini-Symposium, we will review and discuss the most recent findings that link zinc to synaptic function as well as the injurious effects of zinc dyshomeostasis within the context of neuronal death associated with major human neurological disorders, including stroke, epilepsy, and Alzheimer's disease. © 2011 the authors.
Adlard P.A.,University of Melbourne |
Parncutt J.,The Mental Health Research Institute |
Lal V.,The Mental Health Research Institute |
James S.,Australian Synchrotron |
And 4 more authors.
Neurobiology of Disease | Year: 2015
Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6 weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95; AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippocampus. While we demonstrated a small regional increase in hippocampal zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippocampal formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease. © 2014 Elsevier Inc.
Boon W.C.,Florey Neuroscience Institute |
van den Buuse M.,The Mental Health Research Institute |
Wegener N.,The Mental Health Research Institute |
Martin S.,The Mental Health Research Institute |
And 7 more authors.
Behavioural Brain Research | Year: 2010
The aim of this study was to characterize APPC100.V717F transgenic (TgC100.V717F) mice which over-express a mutant C100 fragment of the amyloid precursor protein. The mice were compared to TgC100 wild type mice (TgC100.WT) and non-transgenic controls at 4-9 and 16-22 months of age. TgC100.V717F mice showed behavioural hyperactivity, particularly at a younger age, as shown by increased numbers of elevated plus maze arm entries and Y-maze arm entries, enhanced baseline locomotor activity in the open field, and enhanced amphetamine-induced hyperlocomotion. This hyperactivity was less pronounced in TgC100.WT which only displayed significant differences to non-transgenic controls at a younger age for the number of Y-maze arm entries and baseline locomotor activity in the open field. In addition, TgC100.V717F mice, but not TgC100.WT, demonstrated cognitive deficits, as shown by reduced spontaneous alternation in the Y-maze and markedly reduced retention in a passive avoidance test. At an older age, TgC100.V717F mice showed enhanced startle and increased immobility time in the forced swim test. In the TgC100.V717F mice, but not TgC100.WT, the behavioural changes were paralleled by a significant reduction in the expression of hippocampal NMDA receptor subunits types 1 and 2A. Concomitantly, we detected axonal disruption and apoptosis in the hippocampus of TgC100.V717F mice. In conclusion, these data demonstrate that the mutant C100 fragment is an effector of biochemical and both cognitive and non-cognitive behaviours. These transgenic mice may be a model for the psychotic features associated with early Alzheimer's disease. © 2010 Elsevier B.V. All rights reserved.
Fodero-Tavoletti M.T.,University of Melbourne |
Brockschnieder D.,Bayer AG |
Villemagne V.L.,Austin Health |
Villemagne V.L.,The Mental Health Research Institute |
And 11 more authors.
Nuclear Medicine and Biology | Year: 2012
Purpose: Amyloid-β (Aβ) plaques are a major pathological hallmark of Alzheimer's disease (AD). The noninvasive detection of Aβ plaques may increase the accuracy of clinical diagnosis as well as monitor therapeutic interventions. While [ 11C]-PiB is the most widely used Aβ positron emission tomography (PET) radiotracer, due to the short half-life of 11C (20min), its application is limited to centers with an on-site cyclotron and 11C radiochemistry expertise. Therefore, novel [ 18F] (half-life 110min)-labeled Aβ PET tracers have been developed. We have demonstrated that [ 18F]-florbetaben-PET can differentiate individuals diagnosed with AD from healthy elderly, Parkinson's disease and frontotemporal lobe dementia (FTLD-tau) patients. While [ 18F]-florbetaben-PET retention matched the reported postmortem distribution of Aβ plaques, the nature of [ 18F]-florbetaben binding to other pathological lesions comprising misfolded proteins needs further assessment. The objective of this study was to determine whether Florbetaben selectively binds to Aβ plaques in postmortem tissue specimens containing mixed pathological hallmarks (i.e., tau and α-synuclein aggregates). Method: Human AD, FTLD-tau and dementia with Lewy bodies (DLB) brain sections were analyzed by [ 18F]-florbetaben autoradiography and [ 3H]-florbetaben high-resolution emulsion autoradiography and [ 19F]-florbetaben fluorescence microscopy. Results: Both autoradiographical analyses demonstrated that Florbetaben exclusively bound Aβ plaques in AD brain sections at low nanomolar concentrations. Furthermore, at concentrations thousand-folds higher than those during a PET scan, [ 19F]-florbetaben did not bind to α-synuclein or tau aggregates in DLB and FTLD-tau brain sections, respectively. Detection of [ 19F]-florbetaben staining by fluorescence microscopy in several AD brain regions demonstrated that Florbetaben identified Aβ plaques in all brain regions examined. Conclusion: This study provides further evidence that [ 18F]-florbetaben-PET is a highly selective radiotracer to assess Aβ plaque deposition in the brain. © 2012 Elsevier Inc.
Dean B.,The Mental Health Research Institute |
Dean B.,University of Melbourne |
Tawadros N.,The Mental Health Research Institute |
Tawadros N.,University of Melbourne |
And 4 more authors.
Journal of Affective Disorders | Year: 2010
Background: From studies in the periphery, changed levels of tumour necrosis factor (TNF) have been implicated in the pathophysiology of major depressive disorders (MDD). Therefore we decided to determine whether TNF was altered in the frontal cortex (Brodmann's areas (BA) 24 and 46) from 10 subjects with MDD and 10 control subjects. Methods: Tissue homogenates were prepared from the left hemisphere and levels of TNF trans-membrane (tmTNF) and TNF soluble (sTNF) forms measured by Western blots. Results: tmTNF was significantly increased in BA 46 (mean ± SEM: 7.70 ± 0.92 vs. 3.18 ± 0.87 Ratio Internal Control, p < 0.001), but not BA 24, from subjects with MDD, there was no change in levels of sTNF in either CNS region. Limitations: As the report of tmTNF in postmortem CNS from subjects with MDD, our findings need to be replicated in another group of cases. Conclusions: Our data supports the hypothesis that changes in pro-inflammatory pathways may be involved in the pathophysiology of MDD. Targeting these pathways may be a new approach to treating the disorder. © 2009 Elsevier B.V. All rights reserved.
Rowe C.C.,Austin Health |
Ellis K.A.,University of Melbourne |
Ellis K.A.,The Mental Health Research Institute |
Ellis K.A.,National Ageing Research Institute |
And 21 more authors.
Neurobiology of Aging | Year: 2010
The Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, a participant of the worldwide Alzheimer's Disease Neuroimaging Initiative (ADNI), performed 11C-Pittsburgh Compound B (PiB) scans in 177 healthy controls (HC), 57 mild cognitive impairment (MCI) subjects, and 53 mild Alzheimer's disease (AD) patients. High PiB binding was present in 33% of HC (49% in ApoE-ε4 carriers vs 21% in noncarriers) and increased with age, most strongly in ε4 carriers. 18% of HC aged 60-69 had high PiB binding rising to 65% in those over 80 years. Subjective memory complaint was only associated with elevated PiB binding in ε4 carriers. There was no correlation with cognition in HC or MCI. PiB binding in AD was unrelated to age, hippocampal volume or memory. Beta-amyloid (Aβ) deposition seems almost inevitable with advanced age, amyloid burden is similar at all ages in AD, and secondary factors or downstream events appear to play a more direct role than total beta amyloid burden in hippocampal atrophy and cognitive decline. © 2010.
Adlard P.A.,The Mental Health Research Institute |
Adlard P.A.,University of Melbourne |
Bica L.,University of Melbourne |
White A.R.,University of Melbourne |
And 9 more authors.
PLoS ONE | Year: 2011
We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p = 0.005), spinophilin (+37%, p = 0.04), NMDAR1A (+126%, p = 0.02), NMDAR2A (+70%, p = 0.05), pro-BDNF (+19%, p = 0.02) and BDNF (+19%, p = 0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p = 0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimer's disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular β-amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function. © 2011 Adlard et al.
PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: PloS one | Year: 2011
We have previously demonstrated that brief treatment of APP transgenic mice with metal ionophores (PBT2, Prana Biotechnology) rapidly and markedly improves learning and memory. To understand the potential mechanisms of action underlying this phenomenon we examined hippocampal dendritic spine density, and the levels of key proteins involved in learning and memory, in young (4 months) and old (14 months) female Tg2576 mice following brief (11 days) oral treatment with PBT2 (30 mg/kg/d). Transgenic mice exhibited deficits in spine density compared to littermate controls that were significantly rescued by PBT2 treatment in both the young (+17%, p<0.001) and old (+32%, p<0.001) animals. There was no effect of PBT2 on spine density in the control animals. In the transgenic animals, PBT2 treatment also resulted in significant increases in brain levels of CamKII (+57%, p=0.005), spinophilin (+37%, p=0.04), NMDAR1A (+126%, p=0.02), NMDAR2A (+70%, p=0.05), pro-BDNF (+19%, p=0.02) and BDNF (+19%, p=0.04). While PBT2-treatment did not significantly alter neurite-length in vivo, it did increase neurite outgrowth (+200%, p=0.006) in cultured cells, and this was abolished by co-incubation with the transition metal chelator, diamsar. These data suggest that PBT2 may affect multiple aspects of snaptic health/efficacy. In Alzheimers disease therefore, PBT2 may restore the uptake of physiological metal ions trapped within extracellular -amyloid aggregates that then induce biochemical and anatomical changes to improve cognitive function.
PubMed | The Mental Health Research Institute
Type: Journal Article | Journal: Cell metabolism | Year: 2010
The insulin-like signaling (ILS) pathway regulates metabolism and is known to modulate adult life span in C. elegans. Altered stress responses and resistance to a wide range of stressors are also associated with changes in ILS and contribute to enhanced longevity. The transcription factors DAF-16 and HSF-1 are key effectors of the longevity phenotype. We demonstrate that increased intrinsic thermotolerance, due to lower ILS, is not dependent on stress-induced transcriptional responses but instead requires active protein translation. Translation profiling experiments reveal genes that are posttranscriptionally regulated in response to altered ILS during heat shock in a DAF-16-dependent manner. Furthermore, several novel proteins are specifically required for ILS effects on thermotolerance. We propose that lowered ILS results in metabolic and physiological changes. These DAF-16-induced changes precondition a translational response under acute stress to modulate survival.