A novel crosslinking protocol stabilizes amyloid ß oligomers capable of inducing Alzheimer's-associated pathologies.

Amyloid ß oligomers (AßOs) accumulate early in Alzheimer's disease (AD) and experimentally cause memory dysfunction and the major pathologies associated with AD, for example, tau abnormalities, synapse loss, oxidative damage, and cognitive dysfunction. In order to develop the most effective AßO-targeting diagnostics and therapeutics, the AßO structures contributing to AD-associated toxicity must be elucidated. Here, we investigate the structural properties and pathogenic relevance of AßOs stabilized by the bifunctional crosslinker 1,5-difluoro-2,4-dinitrobenzene (DFDNB). We find that DFDNB stabilizes synthetic Aß in a soluble oligomeric conformation. With DFDNB, solutions of Aß that would otherwise convert to large aggregates instead yield solutions of stable AßOs, predominantly in the 50-300 kDa range, that are maintained for at least 12 days at 37°C. Structures were determined by biochemical and native top-down mass spectrometry analyses. Assayed in neuronal cultures and i.c.v.-injected mice, the DFDNB-stabilized AßOs were found to induce tau hyperphosphorylation, inhibit choline acetyltransferase, and provoke neuroinflammation. Most interestingly, DFDNB crosslinking was found to stabilize an AßO conformation particularly potent in inducing memory dysfunction in mice. Taken together, these data support the utility of DFDNB crosslinking as a tool for stabilizing pathogenic AßOs in structure-function studies.

Truncation of the flash-lag effect by a fixed spatial landmark.

The flash-lag effect is a visual illusion where a moving image is perceived to be advanced in its spatial location relative to a flashed image. Multiple studies have shown that the flash-lag effect can be enhanced by increasing the uncertainty of the moving and/or flashed images. However, little is known about the effect of task-irrelevant visual objects on the flash-lag effect. We were interested to see whether a task-irrelevant spatial landmark might reduce uncertainty and hence reduce the flash-lag effect. We placed a fixed bar between moving and flashed bars while measuring the flash-lag effect in six participants. For most participants, the fixed bar substantially truncated the flash-lag effect. The effect was maximal when the fixed bar was aligned with the flashed bar and decreased when the fixed bar was positioned more peripherally. A second experiment with two participants used a smaller fixed bar; the smaller bar had less truncation effect in one participant, while the other participant showed similar truncation regardless of the fixed bar size. Our results support models that place the locus of the flash-lag effect in higher-order brain areas, e.g., the parietal lobe.