Context Affects Quiet Eye Duration and Motor Performance Independent of Cognitive Effort

© 2021 Human Kinetics. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1123/jsep.2020-0026Extensive literature has shown the effect of ‘Quiet Eye’ (QE) on motor performance. However, little attention has been paid to the context in which tasks are executed(independent of anxiety) and the mechanisms that underpin the phenomenon. Here, we aimed to investigate the effects of context (independent of anxiety) on QE and performance while examining if the mechanisms underpinning QE are rooted in cognitive effort. In this study, 21novice participants completed golf putts while pupil dilation, QE duration, and putting accuracy were measured. Results showed putting to win was more accurate compared to the control (no context) condition and QE duration was longer when putting to win or tie a hole compared to control. There was no effect of context on pupil dilation. Results suggest that,while the task was challenging, performance scenarios can enhance representativeness of practice without adding additional load to cognitive resources, even for novice performers.Peer reviewe

LiHo(PO3)4

Lithium holmium(III) polyphosphate(V), LiHo(PO3)4, belongs to the type I of polyphosphates with general formula ALn(PO3)4, where A is a monovalent cation and Ln is a trivalent rare earth cation. In the crystal structure, the polyphosphate chains spread along the b-axis direction, with a repeat period of four tetra­hedra and 21 inter­nal symmetry. The Li and Ho atoms are both located on twofold rotation axes and are surrounded by four and eight O atoms, leading to a distorted tetra­hedral and dodeca­hedral coordination, respectively. The HoO8 polyhedra are isolated from each other, the closest Ho⋯Ho distance being 5.570 (1) Å

Submicromolar Aß42 Reduces Hippocampal Glutamate Receptors and Presynaptic Markers in an Aggregation-Dependent Manner

Synaptic pathology in Alzheimer's disease brains is thought to involve soluble Aß42 peptide. Here, sterile in-cubation in PBS caused small Aß42 oligomer formation as well as heterogeneous, 6E10-immunopositive ag-gregates of 80–100 kDa. The high molecular weight aggregates (H-agg) formed in a time-dependent manner over an extended 30-day period. Interestingly, an inverse relationship between dimeric and H-agg formation was more evident when incubations were performed at 37 °C as compared to 23 °C, thus providing an exper-imental strategy with which to address synaptic compromise produced by the different Aß aggregates. H-agg species formed faster and to higher levels at 37 °C compared to 23 °C, and the two aggregate preparations were evaluated in hippocampal slice cultures, a sensitive system for monitoring synaptic integrity. Applied daily at 80–600 nM for 7 days, the Aß42 preparations caused dose-dependent and aggregation-dependent declines in a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits as well as in presynaptic components. Unlike the synaptic effects, Aß42 induced only trace cellular degeneration that was CA1 speci?c. The 37 °C preparation was less effective at decreasing synaptic markers, corresponding with its reduced levels of Aß42 monomers and dimers. Aß42 dimers decayed signi?cantly faster at 37 °C than 23 °C, and more rapidly than monomers at either temperature. These ?ndings indicate that Aß42 can self-aggregate into potent synaptotoxic oligomers as well as into larger aggregates that may serve to neutralize the toxic formations. These results will add to the growing debate concerning whether high molecular weight Aß complexes that form amyloid plaques are protective through the sequestration of oligomeric species

Protective Effects of Positive Lysosomal Modulation in Alzheimer's Disease Transgenic Mouse Models

Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid ß peptide (Aß) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aß(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aß pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1?E9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aß immunostaining as well as Aß(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Aß deposition in 20-22-month APPswe/PS1?E9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aß(1-38) occurs as Aß(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Aß truncation. Associated with Aß clearance Associated with Aß clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aß(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aß pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders

Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

Lysosomes are involved in degrading and recycling cellular ingredients, and their disruption with age may contribute to amyloidogenesis, paired helical filaments (PHFs), and a-synuclein and mutant huntingtin aggregation. Lysosomal cathepsins are upregulated by accumulating proteins and more so by the modulator ZPhe-Ala-diazomethylketone(PADK). Such positive modulators of the lysosomal system have been studied in thewell-characterized hippocampal slice model of protein accumulation that exhibits the pathogenic cascade of tau aggregation, tubulin breakdown, microtubule destabilization, transport failure, and synaptic decline. Activecathepsins were upregulated by PADK; Rab proteins were modified as well, indicating enhanced trafficking, whereas lysosome-associated membrane protein and proteasome markers were unchanged. Lysosomal modulationreduced the pre-existing PHF deposits, restored tubulin structure and transport, and recovered synaptic components. Further proof-of-principle studies used Alzheimer disease mouse models. It was recently reported that systemic PADK administration caused dramatic increases in cathepsin B protein and activity levels, whereas neprilysin, insulin-degrading enzyme, a-secretase, and b-secretase were unaffected by PADK. In the transgenic models, PADK treatment resulted in clearance of intracellular amyloid beta (Ab) peptide and concomitant reduction of extracellular deposits. Production of the less pathogenic Ab1–38 peptide corresponded with decreased levels of Ab1–42, supporting the lysosome’s antiamyloidogenic role through intracellular truncation. Amelioration of synaptic and behavioral deficits also indicates a neuroprotective function of the lysosomalsystem, identifying lysosomal modulation as an avenue for disease-modifying therapies. From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlledstrategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia

Cleavage of the Vesicular Glutamate Transporters Under Excitotoxic Conditions

Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters (VGLUTs), and alterations in the transporters expression directly regulate neurotransmitter release. We investigated changes in VGLUT1 and VGLUT2 protein levels after ischemic and excitotoxic insults. The results show that VGLUT2 is cleaved by calpains after excitotoxic stimulation of hippocampal neurons with glutamate, whereas VGLUT1 is downregulated to a lower extent. VGLUT2 was also cleaved by calpains after oxygen/glucose deprivation (OGD), and downregulated after middle cerebral artery occlusion (MCAO) and intrahippocampal injection of kainate. In contrast, VGLUT1 was not affected after OGD. Incubation of isolated synaptic vesicles with recombinant calpain also induced VGLUT2 cleavage, with a little effect observed for VGLUT1. N-terminal sequencing analysis showed that calpain cleaves VGLUT2 in the C-terminus, at Asn534 and Lys542. The truncated GFP-VGLUT2 forms were found to a great extent in non-synaptic regions along neurites, when compared to GFP-VGLUT2. These findings show that excitotoxic and ischemic insults downregulate VGLUT2, which is likely to affect glutamatergic transmission and cell death, especially in the neonatal period when the transporter is expressed at higher levels

Nuclear Translocation and Calpain-Dependent Reduction of Bcl-2 After Neonatal Cerebral Hypoxia–Ischemia

Apoptosis-related mechanisms are important in the pathophysiology of hypoxic–ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia–ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24 h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms

Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation

Despite the characteristic etiologies and phenotypes, different brain disorders rely on common pathogenic events. Glutamate-induced neurotoxicity is a pathogenic event shared by different brain disorders. Another event occurring in different brain pathological conditions is the increase of the extracellular ATP levels, which is now recognized as a danger and harmful signal in the brain, as heralded by the ability of P2 receptors (P2Rs) to affect a wide range of brain disorders. Yet, how ATP and P2R contribute to neurodegeneration remains poorly defined. For that purpose, we now examined the contribution of extracellular ATP and P2Rs to glutamate-induced neurodegeneration. We found both in vitro and in vivo that ATP/ADP through the activation of P2Y1R contributes to glutamate-induced neuronal death in the rat hippocampus. We found in cultured rat hippocampal neurons that the exposure to glutamate (100 µM) for 30 min triggers a sustained increase of extracellular ATP levels, which contributes to NMDA receptor (NMDAR)-mediated hippocampal neuronal death through the activation of P2Y1R. We also determined that P2Y1R is involved in excitotoxicity in vivo as the blockade of P2Y1R significantly attenuated rat hippocampal neuronal death upon the systemic administration of kainic acid or upon the intrahippocampal injection of quinolinic acid. This contribution of P2Y1R fades with increasing intensity of excitotoxic conditions, which indicates that P2Y1R is not contributing directly

Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions

Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated. Objectives: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop ‘Nutrition for the Ageing Brain: Functional Aspects and Mechanisms’ in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). Conclusion: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age