ORCID Profile
0000-0001-5244-6897
Current Organisation
Flinders University
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Central Nervous System | Signal Transduction | Proteomics and Intermolecular Interactions (excl. Medical Proteomics) | Biochemistry and Cell Biology | Neurosciences
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/873270
Abstract: Both Alzheimer's disease (AD) and frontotemporal dementia (FTD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to the umbrella term “tauopathies” for these conditions, also emphasizing the central role of tau in AD and FTD. Generation of transgenic mouse models expressing human tau in the brain has contributed to the understanding of the pathomechanistic role of tau in disease. To reveal the physiological functions of tau in vivo , several knockout mouse strains with deletion of the tau-encoding MAPT gene have been established over the past decade, using different gene targeting constructs. Surprisingly, when initially introduced tau knockout mice presented with no overt phenotype or malformations. The number of publications using tau knockout mice has recently markedly increased, and both behavioural changes and motor deficits have been identified in aged mice of certain strains. Moreover, tau knockout mice have been instrumental in identifying novel functions of tau, both in cultured neurons and in vivo . Importantly, tau knockout mice have significantly contributed to the understanding of the pathophysiological interplay between A β and tau in AD. Here, we review the literature that involves tau knockout mice to summarize what we have learned so far from depleting tau in vivo .
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-07-2022
Abstract: Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer’s disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. Here, we show that tau phosphorylation is governed by interdependence— a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (threonine-50, threonine-69, and threonine-181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer’s mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.
Publisher: Frontiers Media SA
Date: 08-09-2010
Publisher: BMJ
Date: 12-05-2016
Publisher: Springer Science and Business Media LLC
Date: 07-09-2017
DOI: 10.1038/S41467-017-00618-0
Abstract: Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau −/− ) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau −/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.
Publisher: Wiley
Date: 07-04-2020
DOI: 10.1002/PRO.3854
Publisher: Springer Science and Business Media LLC
Date: 21-10-2014
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.NBD.2022.105783
Abstract: Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-β and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73) cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166) CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an in idual being a progressor (OR 35.3 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.
Publisher: Canadian Science Publishing
Date: 10-2021
Abstract: The microtubule-associated protein tau is a key factor in neurodegenerative proteinopathies and is predominantly found in neuronal axons. However, somatodendritic localization of tau occurs in a subset of pathological and physiological tau. Dendritic tau can localize to post-synapses where it interacts with proteins of the post-synaptic density (PSD) protein PSD-95, a membrane-associated guanylate kinase (MAGUK) scaffold factor for organization of protein complexes within the PSD, to mediate downstream signals. However, the molecular details of this interaction remain unclear. Here, we used interaction mapping in cultured cells to demonstrate that tau interacts with the guanylate kinase (GUK) domain in the C-terminal region of PSD-95. The PSD-95 GUK domain is required for a complex with full-length human tau. Mapping the interaction of the MAGUK core with tau revealed that the microtubule binding repeats 2 and 3 and the proline-rich region contributes to this interaction, while the N- and C-terminal regions of tau inhibit interaction. These results reveal the intramolecular determinants of the protein complex of tau and PSD-95 and increase our understanding of tau interactions regulating neurotoxic signaling at the molecular level.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.NEUROSCIENCE.2022.01.005
Abstract: Persistent improvement of cognitive deficits in Alzheimer's disease (AD), a common form of dementia, is an unattained therapeutic objective. Gene therapy holds promise for treatment of familial and sporadic forms of AD. p38γ, a member of the p38 mitogen-activated protein (MAP) kinase family, inhibits amyloid-β toxicity through regulation of tau phosphorylation. We recently showed that a gene delivery approach increasing p38γ resulted in markedly better learning and memory performance in mouse models of AD at advanced stages of amyloid-β- and tau-mediated cognitive impairment. Notably, low-to-moderate expression of p38γ had beneficial outcomes on cognition. The impact of high levels of p38γ on neuronal function remain unclear. Therefore, we addressed the outcomes of high levels of active p38γ on brain function, by direct injection of p38γ-encoding adeno-associated virus (AAV) into the forebrain of aged mice of an APP transgenic AD mouse model. While motor function in p38γ-expressing APP transgenic mice 2 months post-injection was comparable to control treated APP mice, their activity was markedly reduced in the open field test and included frequent bouts of immobility. Moreover, their learning and memory function was markedly impaired compared to control-treated aged APP mice. These results suggest that high neuronal levels of active p38γ emphasize a stress kinase role of p38γ, perturbing circuit function in motivation, navigation, and spatial learning. Overall, this work shows excessive neuronal p38γ levels can aggravate circuit dysfunction and advises adjustable expression systems will be required for sustainable AD gene therapy based on p38γ activity.
Publisher: Elsevier BV
Date: 2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-02-2017
Publisher: Wiley
Date: 10-02-2012
Publisher: Public Library of Science (PLoS)
Date: 08-12-2011
Publisher: EMBO
Date: 22-08-2022
Abstract: Microtubule‐associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity‐labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo . Tau interactors map onto pathways of cytoskeletal, synaptic vesicle and postsynaptic receptor regulation and show significant enrichment for Parkinson's, Alzheimer's and prion disease. We find that tau interacts with and dose‐dependently reduces the activity of N‐ethylmaleimide sensitive fusion protein (NSF), a vesicular ATPase essential for AMPA‐type glutamate receptor (AMPAR) trafficking. Tau‐deficient (tau −/− ) neurons showed mislocalised expression of NSF and enhanced synaptic AMPAR surface levels, reversible through the expression of human tau or inhibition of NSF. Consequently, enhanced AMPAR‐mediated associative and object recognition memory in tau −/− mice is suppressed by both hippoc al tau and infusion with an NSF‐inhibiting peptide. Pathologic mutant tau from mouse models or Alzheimer's disease significantly enhances NSF inhibition. Our results map neuronal tau interactomes and delineate a functional link of tau with NSF in plasticity‐associated AMPAR‐trafficking and memory.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Public Library of Science (PLoS)
Date: 13-10-2016
Publisher: Wiley
Date: 08-2015
DOI: 10.1111/JNC.12821
Abstract: Immunization is increasingly recognized as a suitable therapeutic avenue for the treatment of neurological diseases such as Alzheimer's disease and other tauopathies. Tau is a key molecular player in these conditions and therefore represents an attractive target for passive immunization approaches. We performed such an approach in two independent tau transgenic mouse models of tauopathy, K369I tau transgenic K3 and P301L tau transgenic pR5 mice. The antibodies we used were either specific for full-length tau or tau phosphorylated at serine 404 (pS404), a residue that forms part of the paired helical filament (PHF)-1 phosphoepitope that characterizes tau neurofibrillary tangles in tauopathies. Although both pS404 antibodies had a similar affinity, they differed in isotype, and only passive immunization with the IgG2a/κ pS404-specific antibody resulted in a lower tangle burden and reduced phosphorylation of tau at the PHF1 epitope in K3 mice. In pR5 mice, the same antibody led to a reduced phosphorylation of the pS422 and PHF1 epitopes of tau. In addition, histological sections of the hippoc al dentate gyrus of the immunized pR5 mice displayed reduced pS422 staining intensities. These results show that passive immunization targeting tau can modulate aspects of tau pathology in tau transgenic mouse models, in an antibody isotype-specific manner. We show that passive immunization targeting the pathological phosphorylation site pS404 on human tau with a monoclonal IgG2a/κ, but not a IgG1/κ antibody, reduced hyperphosphorylation of tau and tangle burden in two independent mouse models of tau pathology. This shows that both specificity and isotype of phospho-tau (p-tau)-specific antibodies are important for therapeutically ameliorating tau pathology.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-11-2016
Abstract: Alzheimer's disease presents with amyloid-β (Aβ) plaques and tau tangles. The prevailing idea in the field is that Aβ induces phosphorylation of tau, which in turn mediates neuronal dysfunction. Working in Alzheimer's disease mouse models, Ittner et al. found evidence for a protective role of tau in early Alzheimer's disease. This protection involves specific tau phosphorylation at threonine 205 at the postsynapse. A protective role of phosphorylated tau in disease challenges the dogma that tau phosphorylation only mediates toxic processes. Science , this issue p. 904
Publisher: Springer Science and Business Media LLC
Date: 15-04-2014
DOI: 10.1007/S00125-014-3230-Z
Abstract: Regulation of insulin secretion along the secretory pathway is incompletely understood. We addressed the expression of SIL1, a nucleotide exchange factor for the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78 kD (GRP78), in pancreatic beta cells and investigated whether or not SIL1 is involved in beta cell function. SIL1 expression was analysed by immunoblotting and immunofluorescence. Metabolic and islet variables, including glucose tolerance, beta cell mass, insulin secretion, islet ultrastructure, insulin content and levels of ER stress marker proteins, were addressed in Sil1 knockout (Sil1 (-/-)) mice. Insulin, proinsulin and C-peptide release was addressed in Sil1 (-/-) islets, and SIL1 overexpression or knockdown was explored in MIN6 cells in vitro. Models of type 1 diabetes and insulin resistance were induced in Sil1 (-/-) mice by administration of streptozotocin (STZ) and a high-fat diet (HFD), respectively. We show that SIL1 is expressed in pancreatic beta cells and is required for islet insulin content, islet sizing, glucose tolerance and glucose-stimulated insulin secretion in vivo. Levels of pancreatic ER stress markers are increased in Sil1 (-/-) mice, and Sil1 (-/-) beta cell ER is ultrastructurally compromised. Isolated Sil1 (-/-) islets show lower proinsulin and insulin content and impaired glucose-stimulated insulin secretion. Modulation of SIL1 protein levels in MIN6 cells correlates with changes in insulin content and secreted insulin. Furthermore, Sil1 (-/-) mice are more susceptible to STZ-induced type 1 diabetes with increased apoptosis. Upon HFD feeding, Sil1 (-/-) mice show markedly lower insulin secretion and exacerbated glucose intolerance compared with control mice. Surprisingly, however, HFD-fed Sil1 (-/-) mice display pronounced islet hyperplasia with low amounts of insulin in total pancreas. These results reveal a novel role for the nucleotide exchange factor SIL1 in pancreatic beta cell function under physiological and disease conditions such as diabetes and the metabolic syndrome.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.NEURON.2018.06.003
Abstract: The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer's disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Aβ toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2011
DOI: 10.1007/S00702-011-0626-5
Abstract: Neuropathological features in Alzheimer's Disease (AD) include the presence of hyperphosphorylated forms of the microtubule-associated tau protein (tau) in hippoc al neurones. Numerous studies indicate a neuroprotective effect of calcium-binding proteins (Ca2+ binding proteins) in neurodegenerative diseases (e.g., AD). Secretagogin is a newly described Ca2+ binding protein that is produced by pyramidal neurones of the human hippoc us. Recently, secretagogin expressing hippoc al neurones were demonstrated to resist tau-induced pathology in AD in contrast to the majority of neighbouring neurones. This suggested a neuroprotective effect of secretagogin in hippoc al neurones. Here, we investigated secretagogin expression in wild type (wt) mice as well as in hemizygous and homozygous P301L tau transgenic (tg) mice, which show pronounced and widespread tau pathology in hippoc al neurones. Secretagogin expression was analyzed at the immunohistochemical and biochemical levels in brains of age-matched wt and hemi- and homozygous tau tg mice. In wt mice hippoc al secretagogin-immunoreactive neurones were invariably detected, while immunoreactivity was much lower (P < 0.001) in tau tg mice. Of note, hippoc al secretagogin immunoreactivity was absent in 62.5% of homozygous tau tg mice. In line with this finding, Western blot analysis demonstrated a significant reduction in protein expression levels of secretagogin in homozygous tau tg compared to wt mice. Our results suggest that increased levels of tau negatively influence secretagogin expression in the hippoc us of tau tg mice.
Publisher: Oxford University Press (OUP)
Date: 06-05-2020
Abstract: Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer’s disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippoc us. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of in idual, pathology-harbouring neurons, thereby contributing to memory deficits.
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C6MD00306K
Abstract: Simplified aminothienopyridazine analogues were synthesised and their inhibition of tau protein aggregation assessed.
Publisher: Rockefeller University Press
Date: 05-11-2019
DOI: 10.1084/JEM.20120677
Abstract: Despite their role in resolving inflammatory insults, neutrophils trigger inflammation-induced acute lung injury (ALI), culminating in acute respiratory distress syndrome (ARDS), a frequent complication with high mortality in humans. Molecular mechanisms underlying recruitment of neutrophils to sites of inflammation remain poorly understood. Here, we show that p38 MAP kinase p38δ is required for recruitment of neutrophils into inflammatory sites. Global and myeloid-restricted deletion of p38δ in mice results in decreased alveolar neutrophil accumulation and attenuation of ALI. p38δ counteracts the activity of its downstream target protein kinase D1 (PKD1) in neutrophils and myeloid-restricted inactivation of PKD1 leads to exacerbated lung inflammation. Importantly, p38δ and PKD1 conversely regulate PTEN activity in neutrophils, thereby controlling their extravasation and chemotaxis. PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. Thus, aberrant p38δ–PKD1 signaling in neutrophils may underlie development of ALI and life-threatening ARDS in humans.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NEUBIOREV.2017.01.004
Abstract: Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.
Publisher: Society for Neuroscience
Date: 22-10-2019
DOI: 10.1523/JNEUROSCI.0524-19.2019
Abstract: Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippoc al S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid β (Aβ) formation from amyloid precursor protein (APP) in vitro . To determine whether loss of S1P sensitizes to Aβ-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP SwInd ) mice. SK2 deficiency greatly reduced Aβ content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippoc al electroencephalography. However, several key measures of APP SwInd -dependent neurodegeneration were enhanced on the SK2-null background, despite reduced Aβ burden. These included hippoc al volume loss, oligodendrocyte attrition and myelin loss, and impaired performance in Y-maze and social novelty memory tests. Inhibition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glial cells, linking loss of SK2 activity and S1P in AD to perturbed endosomal lipid metabolism. Our findings establish SK2 as an important endogenous regulator of both APP processing to Aβ, and oligodendrocyte survival, in vivo . These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD. SIGNIFICANCE STATEMENT Genetic, neuropathological, and functional studies implicate both Aβ and altered lipid metabolism and/or signaling as key pathogenic drivers of Alzheimer's disease. In this study, we first demonstrate that the enzyme SK2, which generates the signaling lipid S1P, is required for Aβ formation from APP in vivo . Second, we establish a new role for SK2 in the protection of oligodendrocytes and myelin. Loss of SK2 sensitizes to Aβ-mediated neurodegeneration by attenuating oligodendrocyte survival and promoting hippoc al atrophy, despite reduced Aβ burden. Our findings support a model in which Aβ-independent sensitizing influences such as loss of neuroprotective S1P are more important drivers of neurodegeneration than gross Aβ concentration or plaque density.
Publisher: EMBO
Date: 11-09-2012
Publisher: Wiley
Date: 22-06-2011
DOI: 10.1002/IUB.467
Abstract: Both Alzheimer's disease (AD) and almost every second case of frontotemporal lobar degeneration (FTLD) are characterized by the deposition of hyperphosphorylated forms of the microtubule-associated protein tau in neurons and/or glia. This unifying pathology led to coining the umbrella term "tauopathies" for these conditions. While the deposition of tau ultimately results in the formation of typical histopathological lesions, such as the neurofibrillary tangles (NFTs) in AD, it is now well accepted that tau interferes with normal functions in neurons already before its deposition. Together with the identification of pathogenic mutations in the tau-encoding gene MAPT in FTLD and evidence from a rising number of in vivo animal models a central role of tau in neurodegeneration has emerged. Here, we review the role of pathological tau in axonal transport, mitochondrial respiration, and in mediating amyloid-β toxicity in AD. Furthermore, we review recent findings regarding the spreading of tau pathology throughout the brain as disease progresses.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2020
DOI: 10.1038/S41598-020-70845-X
Abstract: Antibodies have been explored extensively as a potential therapeutic for Alzheimer’s disease, where amyloid-β (Aβ) peptides and the tau protein deposit in patient brains. While the major focus of antibody-based therapy development was on Aβ, arguably with limited success in clinical trials, targeting tau has become an emerging strategy, possibly extending therapies to dementias with isolated tau pathology. Interestingly, low titres of autoantibodies to pathological tau have been described in humans and transgenic mouse models, but their pathophysiological relevance remained elusive. Here, we used two independent approaches to deplete the B-cell lineage and hence antibody formation in human P301S mutant tau transgenic mice, TAU58/2. TAU58/2 mice were either crossed with the B-cell-deficient Ighm knockout line (muMT −/− ) or treated with anti-CD20 antibodies that target B-cell precursors. In both models, B-cell depletion significantly reduced astrocytosis in TAU58/2 mice. Only when B-cells were absent throughout life, in TAU58/2.muMT −/− mice, were spatial learning deficits moderately aggravated while motor performance improved as compared to B-cell-competent TAU58/2 mice. This was associated with changes in brain region-specific tau solubility. No other relevant behavioural or neuropathological changes were observed in TAU58/2 mice in the absence of B-cells/antibodies. Taken together, our data suggests that the presence of antibodies throughout life contributes to astrocytosis in TAU58/2 mice and limits learning deficits, while other deficits and neuropathological changes appear to be independent of the presence of B-cells/antibodies.
Publisher: EMBO
Date: 08-10-2010
Publisher: Springer Science and Business Media LLC
Date: 24-09-2018
DOI: 10.1038/S41598-018-32592-Y
Abstract: Modulation of behavioural responses by neuronal signalling pathways remains incompletely understood. Signalling via mitogen-activated protein (MAP) kinase cascades regulates multiple neuronal functions. Here, we show that neuronal p38α, a MAP kinase of the p38 kinase family, has a critical and specific role in modulating anxiety-related behaviour in mice. Neuron-specific p38α -knockout mice show increased levels of anxiety in behaviour tests, yet no other behavioural, cognitive or motor deficits. Using CRISPR-mediated deletion of p38α in cells, we show that p38α inhibits c-Jun N-terminal kinase (JNK) activity, a function that is specific to p38α over other p38 kinases. Consistently, brains of neuron-specific p38α -knockout mice show increased JNK activity. Inhibiting JNK using a specific blood-brain barrier-permeable inhibitor reduces JNK activity in brains of p38α -knockout mice to physiological levels and reverts anxiety behaviour. Thus, our results suggest that neuronal p38α negatively regulates JNK activity that is required for specific modulation of anxiety-related behaviour.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEULET.2016.08.007
Abstract: Frontotemporal dementia (FTD) presents clinically with behavioral changes including disinhibition. Mutations in the tau-encoding MAPT gene identified in familial cases of FTD have been used to generate transgenic mouse models of the human condition. Here, we report behavioral changes in a recently developed P301S mutant tau transgenic mouse, including disinhibition-like behavior in the elevated plus maze and hyperactivity in the open field arena. Furthermore, histological analysis revealed the amygdala as a primary and early site of pathological tau deposition in these mice. Taken together, neuropathological and behavioral changes in P301S tau transgenic mice resemble features of human FTD.
Start Date: 2017
End Date: 12-2019
Amount: $348,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 10-2024
Amount: $793,836.00
Funder: Australian Research Council
View Funded ActivityStart Date: 05-2022
End Date: 05-2026
Amount: $720,000.00
Funder: Australian Research Council
View Funded Activity