Florey Department of Neuroscience and Mental Health - Research Publications
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ItemNo Preview AvailableCu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice(MDPI, 2023-08)P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD.
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ItemNo Preview AvailableInvestigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study(AMER SOC NEURORADIOLOGY, 2023-06-22)BACKGROUND AND PURPOSE: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. MATERIALS AND METHODS: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. RESULTS: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. CONCLUSIONS: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.
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ItemNo Preview AvailableInvestigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study(BMC, 2023-08-21)BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.
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ItemNo Preview AvailableStriking a NRF2: The Rusty and Rancid Vulnerabilities Toward Ferroptosis in Alzheimer's Disease(MARY ANN LIEBERT, INC, 2023-07-01)Significance: The lack of disease-modifying treatments for Alzheimer's disease (AD) that substantially alter the course of the disease highlights the need for new biological models of disease progression and neurodegeneration. Oxidation of macromolecules within the brain, including lipids, proteins, and DNA, is believed to contribute to AD pathophysiology, concomitant with dysregulation of redox-active metals, such as iron. Creating a unified model of pathogenesis and progression underpinned by iron dysregulation and redox dysregulation in AD could lead to new therapeutic targets with disease-modifying potential. Recent Advances: Ferroptosis, which was named in 2012, is a necrotic form of regulated cell death that depends on both iron and lipid peroxidation. While it is distinct from other types of regulated cell death, ferroptosis is regarded as being mechanistically synonymous with oxytosis. The ferroptosis paradigm has great explanatory potential in describing how neurons degenerate and die in AD. At the molecular level, ferroptosis is executed by the lethal accumulation of phospholipid hydroperoxides generated by the iron-dependent peroxidation of polyunsaturated fatty acids, while the major defensive protein against ferroptosis is the selenoenzyme, glutathione peroxidase 4 (GPX4). An expanding network of protective proteins and pathways have also been identified to complement GPX4 in the protection of cells against ferroptosis, with a central role emerging for nuclear factor erythroid 2-related factor 2 (NRF2). Critical Issues: In this review, we provide a critical overview of the utility of ferroptosis and NRF2 dysfunction in understanding the iron- and lipid peroxide-associated neurodegeneration of AD. Future Directions: Finally, we discuss how the ferroptosis paradigm in AD is providing a new spectrum of therapeutic targets. Antioxid. Redox Signal. 39, 141-161.
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ItemNo Preview AvailableExploring the significance of lipids in Alzheimer's disease and the potential of extracellular vesicles(WILEY, 2023-08-31)Lipids play a significant role in maintaining central nervous system (CNS) structure and function, and the dysregulation of lipid metabolism is known to occur in many neurological disorders, including Alzheimer's disease. Here we review what is currently known about lipid dyshomeostasis in Alzheimer's disease. We propose that small extracellular vesicle (sEV) lipids may provide insight into the pathophysiology and progression of Alzheimer's disease. This stems from the recognition that sEV likely contributes to disease pathogenesis, but also an understanding that sEV can serve as a source of potential biomarkers. While the protein and RNA content of sEV in the CNS diseases have been studied extensively, our understanding of the lipidome of sEV in the CNS is still in its infancy.
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ItemRegional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance(WILEY, 2021-07-01)OBJECTIVE: This paper is a proposal for an update of the iron hypothesis of Alzheimer's disease (AD), based on large-scale emerging evidence. BACKGROUND: Iron featured historically early in AD research efforts for its involvement in the amyloid and tau proteinopathies, APP processing, genetics, and one clinical trial, yet iron neurochemistry remains peripheral in mainstream AD research. Much of the effort investigating iron in AD has focused on the potential for iron to provoke the onset of disease, by promoting proteinopathy though increased protein expression, phosphorylation, and aggregation. NEW/UPDATED HYPOTHESIS: We provide new evidence from a large post mortem cohort that brain iron levels within the normal range were associated with accelerated ante mortem disease progression in cases with underlying proteinopathic neuropathology. These results corroborate recent findings that argue for an additional downstream role for iron as an effector of neurodegeneration, acting independently of tau or amyloid pathologies. We hypothesize that the level of tissue iron is a trait that dictates the probability of neurodegeneration in AD by ferroptosis, a regulated cell death pathway that is initiated by signals such as glutathione depletion and lipid peroxidation. MAJOR CHALLENGES FOR THE HYPOTHESIS: While clinical biomarkers of ferroptosis are still in discovery, the demonstration of additional ferroptotic correlates (genetic or biomarker derived) of disease progression is required to test this hypothesis. The genes implicated in familial AD are not known to influence ferroptosis, although recent reports on APP mutations and apolipoprotein E allele (APOE) have shown impact on cellular iron retention. Familial AD mutations will need to be tested for their impact on ferroptotic vulnerability. Ultimately, this hypothesis will be substantiated, or otherwise, by a clinical trial of an anti-ferroptotic/iron compound in AD patients. LINKAGE TO OTHER MAJOR THEORIES: Iron has historically been linked to the amyloid and tau proteinopathies of AD. Tau, APP, and apoE have been implicated in physiological iron homeostasis in the brain. Iron is biochemically the origin of most chemical radicals generated in biochemistry and thus closely associated with the oxidative stress theory of AD. Iron accumulation is also a well-established consequence of aging and inflammation, which are major theories of disease pathogenesis.
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ItemATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism(SPRINGER, 2022-09-29)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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ItemCopper bis(thiosemicarbazone) complexes modulate P-glycoprotein expression and function in human brain microvascular endothelial cells(WILEY, 2022-04-09)P-glycoprotein (P-gp) is an efflux transporter at the blood-brain barrier (BBB) that hinders brain access of substrate drugs and clears endogenous molecules such as amyloid beta (Aβ) from the brain. As biometals such as copper (Cu) modulate many neuronal signalling pathways linked to P-gp regulation, it was hypothesised that the bis(thiosemicarbazone) (BTSC) Cu-releasing complex, copper II glyoxal bis(4-methyl-3-thiosemicarbazone) (CuII [GTSM]), would enhance P-gp expression and function at the BBB, while copper II diacetyl bis(4-methyl-3-thiosemicarbazone) (CuII [ATSM]), which only releases Cu under hypoxic conditions, would not modulate P-gp expression. Following treatment with 25-250 nM CuII (BTSC)s for 8-48 h, expression of P-gp mRNA and protein in human brain endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively. P-gp function was assessed by measuring accumulation of the fluorescent P-gp substrate, rhodamine 123 and intracellular Cu levels were quantified by inductively coupled plasma mass spectrometry. Interestingly, CuII (ATSM) significantly enhanced P-gp expression and function 2-fold and 1.3-fold, respectively, whereas CuII (GTSM) reduced P-gp expression 0.5-fold and function by 200%. As both compounds increased intracellular Cu levels, the effect of different BTSC backbones, independent of Cu, on P-gp expression was assessed. However, only the Cu-ATSM complex enhanced P-gp expression and this was mediated partly through activation (1.4-fold) of the extracellular signal-regulated kinase 1 and 2, an outcome that was significantly attenuated in the presence of an inhibitor of the mitogen-activated protein kinase regulatory pathway. Our findings suggest that CuII (ATSM) and CuII (GTSM) have the potential to modulate the expression and function of P-gp at the BBB to impact brain drug delivery and clearance of Aβ.
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ItemReceptor-Independent Anti-Ferroptotic Activity of TrkB Modulators(MDPI, 2022-12-01)Dysregulated brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signalling is implicated in several neurodegenerative diseases, including Alzheimer's disease. A failure of neurotrophic support may participate in neurodegenerative mechanisms, such as ferroptosis, which has likewise been implicated in this disease class. The current study investigated whether modulators of TrkB signalling affect ferroptosis. Cell viability, C11 BODIPY, and cell-free oxidation assays were used to observe the impact of TrkB modulators, and an immunoblot assay was used to detect TrkB expression. TrkB modulators such as agonist BDNF, antagonist ANA-12, and inhibitor K252a did not affect RSL3-induced ferroptosis sensitivity in primary cortical neurons expressing detectable TrkB receptors. Several other modulators of the TrkB receptor, including agonist 7,8-DHF, activator phenelzine sulphate, and inhibitor GNF-5837, conferred protection against a range of ferroptosis inducers in several immortalised neuronal and non-neuronal cell lines, such as N27 and HT-1080 cells. We found these immortalised cell lines lack detectable TrkB receptor expression, so the anti-ferroptotic activity of these TrkB modulators was most likely due to their inherent radical-trapping antioxidant properties, which should be considered when interpreting their experimental findings. These modulators or their variants could be potential anti-ferroptotic therapeutics for various diseases.
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ItemNo Preview AvailableCSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers(BMJ PUBLISHING GROUP, 2023-03)BACKGROUND: A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. RESULTS: In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. CONCLUSIONS: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.