Breaking the Cycle, Cholesterol Cycling, and Synapse Damage in Response to Amyloid-ß

Soluble amyloid-β (Aβ) oligomers, a key driver of pathogenesis in Alzheimer disease, bind to cellular prion proteins (PrPC) expressed on synaptosomes resulting in increased cholesterol concentrations, movement of cytoplasmic phospholipase A2 (cPLA2) to lipid rafts and activation of cPLA2. The formation of Aβ-PrPC-cPLA2 complexes was controlled by the cholesterol ester cycle. Thus, Aβ activated cholesterol ester hydrolases which released cholesterol from stores of cholesterol esters; the increased cholesterol concentrations stabilised Aβ-PrPC-cPLA2 complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Aβ-PrPC-cPLA2. In cultured neurons, the cholesterol ester cycle regulated Aβ-induced synapse damage; inhibition of cholesterol ester hydrolases protected neurons, whereas inhibition of cholesterol esterification increased the Aβ-induced synapse damage. Here, I speculate that a failure to deactivate signalling pathways can lead to pathology. Consequently, the esterification of cholesterol is a key factor in the dispersal of Aβ-induced signalling platforms and synapse degeneration

cAMP-Inhibits Cytoplasmic Phospholipase A(2) and Protects Neurons against Amyloid-beta-Induced Synapse Damage

A key event in Alzheimer’s disease (AD) is the production of amyloid-β (Aβ) peptides and the loss of synapses. In cultured neurons Aβ triggered synapse damage as measured by the loss of synaptic proteins. α-synuclein (αSN), aggregates of which accumulate in Parkinson’s disease, also caused synapse damage. Synapse damage was associated with activation of cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates synapse function and structure, and the production of prostaglandin (PG) E2. In synaptosomes PGE2 increased concentrations of cyclic adenosine monophosphate (cAMP) which suppressed the activation of cPLA2 demonstrating an inhibitory feedback system. Thus, Aβ/αSN-induced activated cPLA2 produces PGE2 which increases cAMP which in turn suppresses cPLA2 and, hence, its own production. Neurons pre-treated with pentoxifylline and caffeine (broad spectrum phosphodiesterase (PDE) inhibitors) or the PDE4 specific inhibitor rolipram significantly increased the Aβ/αSN-induced increase in cAMP and consequently protected neurons against synapse damage. The addition of cAMP analogues also inhibited cPLA2 and protected neurons against synapse damage. These results suggest that drugs that inhibit Aβ-induced activation of cPLA2 and cross the blood–brain barrier may reduce synapse damage in AD

Glycosylphosphatidylinositols: More than just an anchor?

There is increasing interest in the role of glycosylphosphatidylinositol (GPI) anchors that attach some proteins to cell membranes. Far from being biologically inert, GPIs influence the targeting, intracellular trafficking and function of the attached protein. Our recent paper demonstrated the role of sialic acid on the GPI of the cellular prion protein (PrPC). The “prion diseases” arise following the conversion of PrPC to a disease-associated isoform called PrPSc or “prion”. Our paper showed that desialylated PrPC inhibited PrPSc formation. Aggregated PrPSc creates a signaling platform in the cell membrane incorporating and activating cytoplasmic phospholipase A2 (cPLA2), an enzyme that regulates PrPC trafficking and hence PrPSc formation. The presence of desialylated PrPC caused the dissociation of cPLA2 from PrP-containing platforms, reduced the activation of cPLA2 and inhibited PrPSc production. We concluded that sialic acid contained within the GPI attached to PrPC modifies local membrane microenvironments that are important in PrP-mediated cell signaling and PrPSc formation

The thermodynamics of collapsing molecular cloud cores using smoothed particle hydrodynamics with radiative transfer

We present the results of a series of calculations studying the collapse of molecular cloud cores performed using a three-dimensional smoothed particle hydr odynamics code with radiative transfer in the flux-limited diffusion approximation. The opacities and specific heat capacities are identical for each calculation. However, we find that the temperature evolution during the simulations varies significantly when starting from different initial conditions. Even spherically-symmetric clouds with different initial densities show markedly different development. We conclude that simple barotropic equations of state like those used in some previous calculations provide at best a crude approximation to the thermal behaviour of the gas. Radiative transfer is necessary to obtain accurate temperatures.Comment: 8 pages, 9 figures, accepted for publication in MNRA

The effect of magnetic fields on star cluster formation

We examine the effect of magnetic fields on star cluster formation by performing simulations following the self-gravitating collapse of a turbulent molecular cloud to form stars in ideal MHD. The collapse of the cloud is computed for global mass-to-flux ratios of infinity, 20, 10, 5 and 3, that is using both weak and strong magnetic fields. Whilst even at very low strengths the magnetic field is able to significantly influence the star formation process, for magnetic fields with plasma beta < 1 the results are substantially different to the hydrodynamic case. In these cases we find large-scale magnetically-supported voids imprinted in the cloud structure; anisotropic turbulent motions and column density structure aligned with the magnetic field lines, both of which have recently been observed in the Taurus molecular cloud. We also find strongly suppressed accretion in the magnetised runs, leading to up to a 75% reduction in the amount of mass converted into stars over the course of the calculations and a more quiescent mode of star formation. There is also some indication that the relative formation efficiency of brown dwarfs is lower in the strongly magnetised runs due to the reduction in the importance of protostellar ejections.Comment: 16 pages, 9 figures, 8 very pretty movies, MNRAS, accepted. Version with high-res figures + movies available from http://www.astro.ex.ac.uk/people/dprice/pubs/mcluster/index.htm

Transcranial electric stimulation and cognitive training improves face perception

Recently, there has been much interest the effectiveness of cognitive training programmes across a variety of cognitive and perceptual domains. Some evidence suggests that combining training programmes with noninvasive brain stimulation techniques such as transcranial random noise stimulation (tRNS) can enhance training gains, but to date this has only been examined in numerosity and arithmetic tasks. In this study, we examined whether tRNS modulated the effects of a face recognition training programme. Participants completed a face discrimination training task for an hour per day over five days. Each day, training was preceded by twenty minutes of active high frequency tRNS or sham stimulation, targeted at the posterior temporal cortices or the inferior frontal gyri (IFG). Participants who received active stimulation to the posterior temporal cortices showed significant improvement on a facial identity discrimination task (the Cambridge Face Perception Test) after training, whereas those receiving sham or IFG stimulation showed no performance change. There was no evidence of an effect of stimulation on a face memory task (the Cambridge Face Memory Test). These results suggest that tRNS can enhance the effectiveness of cognitive training programmes, but further work is needed to establish whether perceptual gains can be generalised to face memory