Pe Davies

The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein

One of the neuropathological hallmarks of Alzheimers disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau,. Tau is hyperphosphorylated in PHFs,, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly,. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimers disease. Phosphorylation on a serine or threonine that precedes proline (pS/T–P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1 (refs 8,9,10,11, 12,13,14). Pin1 specifically isomerizes pS/T–P bonds and regulates the function of mitotic phosphoproteins,. Here we show that Pin1 binds to only one pT–P motif in tau and co-purifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimers disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimers disease.

Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms

Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimers disease, although this disease is also characterized by NFT formation and cell death. Importantly, the mechanism of tau-mediated neuronal death remains elusive. Aged mice expressing nonmutant human tau in the absence of mouse tau (htau mice) developed NFTs and extensive cell death. The mechanism of neuron death was investigated in htau mice, and surprisingly, the presence of tau filaments did not correlate directly with death within individual cells, suggesting that cell death can occur independently of NFT formation. Our observations show that the mechanism of neurodegeneration involved reexpression of cell-cycle proteins and DNA synthesis, indicating that nonmutant tau pathology and neurodegeneration may be linked via abnormal, incomplete cell-cycle reentry.

Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models REDUCTION OF TAU PATHOLOGY AND DELAY OF DISEASE PROGRESSION

Background: Recent active immunization studies have raised the possibility of modulating Tau pathology. Results: Peripheral administration of two antibodies against pathological Tau forms reduces Tau pathology and improves functional outcomes. Conclusion: Passive immunotherapy is effective at preventing the buildup of intracellular Tau pathology. Significance: Tau immunotherapy should be considered as a therapeutic approach for the treatment of Alzheimer disease and other tauopathies. The microtubule-associated protein Tau plays a critical role in the pathogenesis of Alzheimer disease and several related disorders (tauopathies). In the disease Tau aggregates and becomes hyperphosphorylated forming paired helical and straight filaments, which can further condense into higher order neurofibrillary tangles in neurons. The development of this pathology is consistently associated with progressive neuronal loss and cognitive decline. The identification of tractable therapeutic targets in this pathway has been challenging, and consequently very few clinical studies addressing Tau pathology are underway. Recent active immunization studies have raised the possibility of modulating Tau pathology by activating the immune system. Here we report for the first time on passive immunotherapy for Tau in two well established transgenic models of Tau pathogenesis. We show that peripheral administration of two antibodies against pathological Tau forms significantly reduces biochemical Tau pathology in the JNPL3 mouse model. We further demonstrate that peripheral administration of the same antibodies in the more rapidly progressive P301S tauopathy model not only reduces Tau pathology quantitated by biochemical assays and immunohistochemistry, but also significantly delays the onset of motor function decline and weight loss. This is accompanied by a reduction in neurospheroids, providing direct evidence of reduced neurodegeneration. Thus, passive immunotherapy is effective at preventing the buildup of intracellular Tau pathology, neurospheroids, and associated symptoms, although the exact mechanism remains uncertain. Tau immunotherapy should therefore be considered as a therapeutic approach for the treatment of Alzheimer disease and other tauopathies.

CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects

Abstract—In this longitudinal study of 77 patients with mild cognitive impairment (MCI), the authors analyzed whether levels of tau protein phosphorylated at threonine 231 (p-tau231) in CSF correlate with progression of cognitive decline. High CSF p-tau231 levels at baseline, but not total tau protein levels, correlated with cognitive decline and conversion from MCI to AD. Independently, old age and APOE-&egr;4 carrier status were predictive as well. Our data indicate that an increased p-tau231 level is a potential risk factor for cognitive decline in patients with MCI.

Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease

We studied neocortical morphometry (cortical thickness, neurons, and glia), lesion counts (plaques and tangles), and choline acetyltransferase levels in up to 113 Alzheimer brains and 48 controls. Comparisons between young (under 65) and old (over 70) Alzheimer cases revealed more tangles in the former, but no other statistically significant differences in the measured variables. Differences in these parameters between young Alzheimer cases and young controls were similar to the differences found between old Alzheimer cases and old controls. Linear regression analyses correlating some of these variables with age in Alzheimers disease, considered together with the effects of normal aging on the same parameters, reveal in Alzheimers disease a spectrum of graded pathologic severity inversely proportional to age. Nevertheless, even in advanced old age (80 to 100), significant differences persist in these parameters between very elderly Alzheimer brains and controls.

The Sustainable Rivers Audit: assessing river ecosystem health in the Murray-Darling Basin, Australia

The Sustainable Rivers Audit (SRA) is a systematic assessment of the health of river ecosystems in the Murray–Darling Basin (MDB), Australia. It has similarities to the United States’ Environmental Monitoring and Assessment Program, the European Water Framework Directive and the South African River Health Program, but is designed expressly to represent functional and structural links between ecosystem components, biophysical condition and human interventions in the MDB. Environmental metrics derived from field samples and/or modelling are combined as indicators of condition in five themes (Hydrology, Fish, Macroinvertebrates, Vegetation and Physical Form). Condition indicator ratings are combined using expert-system rules to indicate ecosystem health, underpinned by conceptual models. Reference condition, an estimate of condition had there been no significant human intervention in the landscape, provides a benchmark for comparisons. To illustrate, a synopsis is included of health assessments in 2004–2007. This first audit completed assessments of condition and ecosystem health at the valley scale and in altitudinal zones, and future reports will include trend assessments. SRA river-health assessments are expected to play a key role in future water and catchment management through integration in a Basin Plan being developed by the Murray–Darling Basin Authority for implementation after 2011. For example, there could be links to facilitate monitoring against environmental targets.

Tau phosphorylated at tyrosine 394 is found in Alzheimer's disease tangles and can be a product of the Abl-related kinase, Arg.

Tau is a microtubule-associated protein and a main component of neurofibrillary tangles, one of the pathologic hallmarks of Alzheimers disease. The paired helical filaments (PHF) that comprise neurofibrillary tangles contain an abnormally hyperphosphorylated form of tau. Historically, most of the tau phosphorylation sites that have been characterized are serine and threonine residues. Recent reports state that tau can be phosphorylated at tyrosine residues by kinases including Fyn, Syk, and c-abl (Abl). Proteomic analyses show that tau phosphorylated at tyrosine 394 (Y394) exists within PHF samples taken from Alzheimers disease brains. This study also confirms phosphorylation of Y394 as an Alzheimers disease-specific event by immunohistochemistry. To date, only Abl is known to phosphorylate this particular site on tau. We report, for the first time, that Arg, the other member of the Abl family of tyrosine kinases, also phosphorylates tau at Y394 in a manner independent of Abl activity. Given the reported role of Arg in oxidative stress response and neural development, the ability to phosphorylate tau at Y394 implicates Arg as a potential player in the pathogenesis of Alzheimers disease and other tauopathies.

The toxicology and metabolism of chlorothalonil in fish. I. Lethal levels for Salmo gairdneri, Galaxias maculatus, G. truttaceus and G. auratus and the fate of 14C-TCIN in S. gairdneri

Abstract LC 50 values of chlorothalonil (TCIN) to Salmo gairdneri, Galaxias maculatus , G. truttaceus and G. auratus for 24, 48 and 96 h were determined using a flow-through apparatus. All values were lower than those previously reported for various fish species. The influence of decreased oxygen concentration and co-exposure of acephate on LC 50 values of TCIN to Salmo gairdneri was also investigated. Uptake of 14 C-chlorothalonil in internal organs of Salmo gairdneri was measured during a 96 h exposure to 10 μg/l in water. The primary site of accumulation was the bile. Levels in all other organs were in the mg/kg range and increased with time of exposure. Protein binding was observed in the liver. Release of polar labelled metabolites was constant with time over 96 h depuration, with 0.5% being TCIN. All organ levels dropped during this time. The possible route of TCIN metabolism is discussed.

Ecosystem science: toward a new paradigm for managing Australia's inland aquatic ecosystems.

Freshwater ecosystems are a foundation of our social, cultural, spiritual and economic well being. The degraded condition of many of Australias river ecosystems is testament to our failure to manage these resources wisely. Ecosystem science involves the holistic study of complex biophysical systems to understand the drivers that influence ecological pattern and process. Ecosystem science should underpin both water management and policy. Our understanding of aquatic ecosystems lags behind the increasing problems caused by past land and water management. Current post-graduate training programmes will not provide the aquatic ecosystem scientists needed by government and management agencies to prevent further degradation. We advocate new initiatives to capture the skills, knowledge and innovation of our research community by engaging scientists and managers in large-scale, long-term ecosystem science programmes across Australia and to integrate these programmes with community aspirations, policy, planning and management. We call on management agencies to increase their support for and uptake and use of ecosystem science. We also advocate establishment of national archives for long-term ecologically-relevant data and samples, and clear custodial arrangements to protect, update and facilitate knowledge-transfer. These initiatives need to be supported by more extensive, better-funded post-graduate and post-doctoral programmes in ecosystem science and management.

Catastrophic macroinvertebrate drift and sublethal effects on brown trout, Salmo trutta, caused by cypermethrin spraying on a Tasmanian stream

Abstract Cypermethrin, a pyrethroid insecticide, was aerially sprayed on a Eucalyptus nitens plantation in northern Tasmania, Australia. Several tributary streams of the Meander River draining the plantation received direct spray drift contamination of the order of 0.05 mg/m2. Increases in invertebrate drift of over 200-times were observed on the day of spraying in Sales Rivulet. Drift was significantly elevated for 8 days after spraying, recovering both in density and relative abundance after early winter floods. Plecoptera and ephemeroptera comprised 89–92% of the drift immediately after spraying, compared with 6–21% pre-spraying and at an uncontaminated site. Benthic abundances of plecoptera and ephemeroptera decreased after spraying in all small streams draining the plantation. Early winter floods were observed to facilitate recolonisation at affected sites. Resident Salmo trutta were collected from the streams before and during 6 months after spraying. Plasma chloride, glucose and protein concentrations were not affected by the spraying event. Significant transient changes in muscle RNA/DNA levels as well as brain and muscle acetylcholinesterase levels and hepatic mixed function oxygenase activity were related to the spraying event. These changes commenced around day 7 and persisted until day 26. Changes in fish diet were also observed, related to the sequence of abundant and depauperate invertebrate drift after spraying. Pathological symptoms in fish were apparently related to dietary intake of cypermethrin from dead and dying invertebrate drift.