The amyloid peptides Ab 40 and Ab 42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Ab 42 seems more pathogenic than Ab 40 , the reason for this is not well understood. We show here that small alterations in the Ab 42 :Ab 40 ratio dramatically affect the biophysical and biological properties of the Ab mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Ab 42 :Ab 40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

Influx of Ca 2؉ ions through ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca 2؉ permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca 2؉ ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptormediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.amyotrophic lateral sclerosis ͉ ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor ͉ neurodegeneration ͉ mutant superoxide dismutase 1

The establishment of neuronal connectivity depends on the correct initial polarization of the young neurons. In vivo, developing neurons sense a multitude of inputs and a great number of molecules are described that affect their outgrowth. In vitro, many studies have shown the possibility to influence neuronal morphology and growth by biophysical, i.e. topographic, signaling. In this work we have taken this approach one step further and investigated the impact of substrate topography in the very early differentiation stages of developing neurons, i.e. when the cell is still at the round stage and when the first neurite is forming. For this purpose we fabricated micron sized pillar structures with highly reproducible feature sizes, and analyzed neurons on the interface of flat and topographic surfaces. We found that topographic signaling was able to attract the polarization markers of mouse embryonic neurons -N-cadherin, Golgi-centrosome complex and the first bud were oriented towards topographic stimuli. Consecutively, the axon was also preferentially extending along the pillars. These events seemed to occur regardless of pillar dimensions in the range we examined. However, we found differences in neurite length that depended on pillar dimensions. This study is one of the first to describe in detail the very early response of hippocampal neurons to topographic stimuli.

Microelectrode arrays (MEAs) have proved to be useful tools for characterizing electrically active cells such as cardiomyocytes and neurons. While there exist a number of integrated electronic chips for recording from small populations or even single cells, they rely primarily on the interface between the cells and 2D flat electrodes. Here, an approach that utilizes residual stress‐based self‐folding to create individually addressable multielectrode interfaces that wrap around the cell in 3D and function as an electrical shell‐like recording device is described. These devices are optically transparent, allowing for simultaneous fluorescence imaging. Cell viability is maintained during and after electrode wrapping around the cel and chemicals can diffuse into and out of the self‐folding devices. It is further shown that 3D spatiotemporal recordings are possible and that the action potentials recorded from cultured neonatal rat ventricular cardiomyocytes display significantly higher signal‐to‐noise ratios in comparison with signals recorded with planar extracellular electrodes. It is anticipated that this device can provide the foundation for the development of new‐generation MEAs where dynamic electrode–cell interfacing and recording substitutes the traditional method using static electrodes.

Guidance of neuronal extensions is a complex process essential for linking neurons into complex functional networks underlying the workings of the neural system. Decades of research have suggested the ability of neuronal growth cones to integrate multiple types of cues during the extension process, but also have raised numerous still unanswered questions about synergy or antagonism between the superimposed chemical and mechanical signaling inputs. In this study, using a novel microfabricated analysis platform, we investigate the response of primary mouse embryonic hippocampal neurons to superimposed topographic and soluble chemical cues. We find that an optimal spatial frequency of topographic cues exists, maximizing the precision of the neurite extension. This optimal frequency can help the extending neurites navigate a topographically complex environment, providing pronounced directional selectivity. We also demonstrate that this cue can synergistically enhance attractive and suppress repulsive guidance by the bi-functional soluble cue Netrin-1, and eliminate the repulsive guidance by a chemorepellent Semaphorin3A (Sema3A). These results suggest that topographic cues can provide optimal periodic input into the guidance signaling processes involved in growth cone chemoattraction and can synergistically interact with chemical gradients of soluble guidance cues, shedding light on complex events accompanying the development of the functional nervous system.