Metal chaperones prevent zinc-mediated cognitive decline.

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 6weeks) 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.

Increasing Cu bioavailability inhibits Abeta oligomers and tau phosphorylation.

Cognitive decline in Alzheimer's disease (AD) involves pathological accumulation of synaptotoxic amyloid-beta (Abeta) oligomers and hyperphosphorylated tau. Because recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) activity regulates these neurotoxic pathways, we developed an AD therapeutic strategy to target GSK3beta. The strategy involves the use of copper-bis(thiosemicarbazonoto) complexes to increase intracellular copper bioavailability and inhibit GSK3beta through activation of an Akt signaling pathway. Our lead compound Cu(II)(gtsm) significantly inhibited GSK3beta in the brains of APP/PS1 transgenic AD model mice. Cu(II)(gtsm) also decreased the abundance of Abeta trimers and phosphorylated tau, and restored performance of AD mice in the Y-maze test to levels expected for cognitively normal animals. Improvement in the Y-maze correlated directly with decreased Abeta trimer levels. This study demonstrates that increasing intracellular copper bioavailability can restore cognitive function by inhibiting the accumulation of neurotoxic Abeta trimers and phosphorylated tau.

A multi-centre early evaluation of the effectiveness of workshop teaching to improve the confidence of UK and Irish dental students when addressing patient mental health.

Background Dental practitioners can have low confidence when addressing patient mental health as part of wider patient management. This is increasingly relevant due to the rising prevalence of mental health conditions and the relationship that can exist between mental and oral health. Interactive workshop teaching on patient mental health may enhance the confidence of dental students when addressing mental health conditions in patients. This study trialled workshop teaching as an educational intervention in five UK and Irish dental schools.Methods A quantitative, scenario-based confidence survey to further establish the need for intervention, followed by delivery of a workshop intervention to volunteer participants. Pre- and post-workshop surveys were used to assess the effectiveness of the workshop.Results Survey data showed low confidence among dental students when addressing patient mental health. Workshop intervention improved dental student confidence on average from 2.3-3.7 on a five-point scale, with less than 0.5% likelihood that reported changes in confidence were due to chance.Discussion Low confidence of dental students addressing patient mental health scenarios echoed wider literature findings surrounding dental clinicians' ability to address patient mental health. This further demonstrated the need for educational intervention, with workshop effectiveness demonstrated within this paper.Conclusion Workshop teaching is an effective way to enhance dental student confidence when addressing patient mental health and should be considered for implementation in the Bachelor of Dental Surgery curriculum.

Morphologies and projections of defined classes of neurons in the submucosa of the guinea-pig small intestine.

Four types of neurons have previously been identified by neurochemical markers in the submucosal ganglia of the guinea-pig small intestine, and functional roles have been ascribed to each type. However, morphological differences among the classes have not been determined, and there is only partial information about their projections within the submucosa. In the present work, we used intracellular microelectrodes to fill neurons of each type with biocytin, which was then converted to a permanent dye, so that the shapes of the neurons could be determined and their projections within the submucosa could be followed. Cell bodies of noncholinergic secretomotor/ vasodilator neurons had Dogiel type I morphology. These neurons, which are vasoactive intestinal peptide immunoreactive, had single axons that ran through many ganglia without providing terminals around other neurons. Cholinergic secretomotor neurons with neuropeptide Y immunoreactivity had Stach type IV morphology, and cholinergic secretomotor/vasodilator neurons had stellate cell bodies. The axons of these two types ran short distances in the plexus and did not innervate other submucosal neurons. Neurons of the fourth type, intrinsic primary afferent neurons, had cell bodies with Dogiel type II morphology and their processes supplied networks of varicose processes around other nerve cells. It is concluded that each functionally defined type of submucosal neuron has a characteristic morphology and that intrinsic primary afferent neurons synapse with secretomotor neurons to form monosynaptic secretomotor reflex circuits.

Stereospecific interactions are necessary for Alzheimer disease amyloid-ß toxicity.

Previous studies suggest membrane binding is a key determinant of amyloid ß (Aß) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aß42 (D-Aß42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aß42 (L-Aß42). The results showed D- and L-Aß42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-Aß42 was neurotoxic and inhibited long term potentiation indicating L-Aß42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited L-Aß42 but not D-Aß42 binding to the cultured cortical neurons and significantly rescued L-Aß42 neurotoxicity. This suggests that Aß mediated toxicity in Alzheimer disease is dependent upon Aß binding to phosphatidylserine on neuronal cells.

Stimulus pattern dependence of the Alzheimer's disease amyloid-beta 42 peptide's inhibition of long term potentiation in mouse hippocampal slices.

Increasing evidence has pointed to inhibition of Long Term Potentiation (LTP) by soluble A beta 42 oligomers as central in the etiology of the learning and memory deficits that are hallmarks of Alzheimer Disease. These effects are thought to occur by an interaction between A beta 42 and certain cellular effectors that induce LTP, however, the precise identity of the A beta 42-interactive signaling molecules is unknown. Identification of such effectors is made more difficult because LTP induced by different stimulation protocols can be expressed through heterogeneous signaling pathways. The aim of this study was to compare differences in the A beta 42-dependent levels of inhibition of LTPs that were induced using high frequency stimulation (HFS), versus theta burst stimulation (TBS). Our results show that untreated control brain slices tetanized with either HFS or TBS gave similar levels of LTP and post tetanic stimulation (PTP), suggesting that the response induced by either protocol was comparable. However, A beta 42 peptide significantly blocked LTP and PTP induced by HFS, but not when TBS was used. NMDA receptor antagonists, D-AP5 and ifenprodil, both blocked LTPs that were induced by HFS or TBS. We propose that unknown signaling effectors, other than the NMDA receptor, which are differentially involved in the induction of LTP by TBS, as compared to HFS, may be responsible for this resistance of TBS-induced LTP to A beta 42 dependent inhibition.