Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity

BACKGROUND AND PURPOSE:

Amyloid-ß (Aß) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aß aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aß(1-42) and cell-derived Aß oligomers.
EXPERIMENTAL APPROACH:

Surface plasmon resonance studies measured binding of SEN1269 to Aß(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aß(1-42) -induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aß(1-42) and cell-derived Aß oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.
KEY RESULTS:

SEN1269 demonstrated direct binding to monomeric Aß(1-42) , produced a concentration-related blockade of Aß(1-42) aggregation and protected neuronal cell lines exposed to Aß(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aß(1-42) and cell-derived Aß oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aß oligomers.
CONCLUSIONS AND IMPLICATIONS:

SEN1269 protected cells exposed to Aß(1-42) , displayed central activity with respect to reducing Aß-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aß-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aß-mediated synaptic toxicity as potential neuroprotective agents for treating AD.

On The Energy-Efficiency of Byte-Addressable Non-Volatile Memory

Non-Volatile Memory (NVM) technology holds promise to replace SRAM and DRAM at various levels of the memory hierarchy. The interest in NVM is motivated by the difficulty faced in scaling DRAM beyond 22 nm and, long-term, lower cost per bit. While offering higher density and negligible static power (leakage and refresh), NVM suffers increased latency and energy per memory access. This paper develops energy and performance models of memory systems and applies them to understand the energy-efficiency of replacing or complementing DRAM with NVM. Our analysis focusses on the application of NVM in main memory. We demonstrate that NVM such as STT-RAM and RRAM is energy-efficient for memory sizes commonly employed in servers and high-end workstations, but PCM is not. Furthermore, the model is well suited to quickly evaluate the impact of changes to the model parameters, which may be achieved through optimization of the memory architecture, and to determine the key parameters that impact system-level energy and performance.

Ulster Says Maybe: The Restructuring of Evangelical Politics in Northern Ireland

The recent electoral triumphs of the Democratic Unionist Party (DUP) have stimulated debate about the role of fundamentalist or ‘traditional evangelical’ Protestantism within the party and in Northern Irish politics. This paper argues that a significant restructuring of evangelical politics is taking place, one that is interest group‐centred rather than DUP‐centred. This process has been facilitated by changes in the structure of civil society. Traditional evangelical interest groups are ‘reframing’ their political projects in surprising new ways: abandoning Calvinist conceptions of church and state, using discourses of marginalisation and discrimination, and focusing on ‘moral’ issues. These subtle shifts in rhetoric constitute an acceptance of the post‐Belfast Agreement order. Rather than the tired, ‘Ulster Says No’ politics of the past, evangelicals are speaking out with a pragmatic ‘maybe’. This move parallels and reinforces the DUP’s ideological shifts, and provides an extra‐party platform for evangelicals to impact politics.