The amyloid peptides Aβ40 and Aβ42 of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ42 seems more pathogenic than Aβ40, the reason for this is not well understood. We show here that small alterations in the Aβ42:Aβ40 ratio dramatically affect the biophysical and biological properties of the Aβ 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 Aβ42:Aβ40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Aβ species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Aβ 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.

Neural probes have become the most important tool for enabling neuroscientists to place microelectrode sensors close to individual neurons and to monitor their activity in vivo. With such devices, it is possible to perform acute or chronic extracellular recordings of electrical activity from a single neuron or from groups of neurons. After the many developments in neural implants, it has become clear that large arrays of electrodes are desirable to further investigate the activity performed by complex neural networks. Therefore, in this paper, we propose a CMOS neural probe containing 455 active electrodes in the probe shank (100 μm wide, 10 mm long, and 50 μm thick) and 52 simultaneous readout channels in the probe body (2.9 × 3.3 mm²). In situ amplification under each electrode enables low-impedance interconnection lines, regardless of the electrode impedance, with a residual crosstalk of -44.8 dB. This design has been implemented in a 0.18-μm standard CMOS technology, with additional CMOS-compatible post-processing performed at wafer level to define the electrodes and the probe outline. In this architecture, the analog front-end achieves an input-referred noise of 3.2 μV_rms and an NEF of 3.08. The power consumption of the core circuit is 949.8 μW, while the total power consumption is 1.45 mW. The high-density active-electrode array in this neural probe allows for the massive recording of neural activity. In vivo measurements demonstrate successful simultaneous recordings from many individual cells.

Missense mutations in alanine 673 of the amyloid precursor protein (APP), which corresponds to the second alanine of the amyloid β (Aβ) sequence, have dramatic impact on the risk for Alzheimer disease; A2V is causative, and A2T is protective. Assuming a crucial role of amyloid-Aβ in neurodegeneration, we hypothesized that both A2V and A2T mutations cause distinct changes in Aβ properties that may at least partially explain these completely different phenotypes. Using human APP-overexpressing primary neurons, we observed significantly decreased Aβ production in the A2T mutant along with an enhanced Aβ generation in the A2V mutant confirming earlier data from non-neuronal cell lines. More importantly, thioflavin T fluorescence assays revealed that the mutations, while having little effect on Aβ42 peptide aggregation, dramatically change the properties of the Aβ40 pool with A2V accelerating and A2T delaying aggregation of the Aβ peptides. In line with the kinetic data, Aβ A2T demonstrated an increase in the solubility at equilibrium, an effect that was also observed in all mixtures of the A2T mutant with the wild type Aβ40. We propose that in addition to the reduced β-secretase cleavage of APP, the impaired propensity to aggregate may be part of the protective effect conferred by A2T substitution. The interpretation of the protective effect of this mutation is thus much more complicated than proposed previously.

Interfacing neurons with micro- and nano-electronic devices has been a subject of intense study over the last decade. One of the major problems in assembling efficient neuro-electronic hybrid systems is the weak electrical coupling between the components. This is mainly attributed to the fundamental property of living cells to form and maintain an extracellular cleft between the plasma membrane and any substrate to which they adhere. This cleft shunts the current generated by propagating action potentials and thus reduces the signal-to-noise ratio. Reducing the cleft thickness, and thereby increasing the seal resistance formed between the neurons and the sensing surface, is thus a challenge and could improve the electrical coupling coefficient. Using electron microscopic analysis and field potential recordings, we examined here the use of gold micro-structures that mimic dendritic spines in their shape and dimensions to improve the adhesion and electrical coupling between neurons and micro-electronic devices. We found that neurons cultured on a gold-spine matrix, functionalized by a cysteine-terminated peptide with a number of RGD repeats, readily engulf the spines, forming tight apposition. The recorded field potentials of cultured Aplysia neurons are significantly larger using gold-spine electrodes in comparison with flat electrodes.

In this letter, we demonstrate that organic-based transistors are able to detect charged/uncharged chemical species in aqueous media via the field effect. The chemical sensitivity of the organic transistors is illustrated for protons and glucose. The electrochemical potential developed at the solution/dielectric interface depends on the proton concentration in solution and it modifies the current flowing in the transistor according to this concentration. Glucose can also be detected if an enzymatic layer is coupled to the dielectric surface. An inorganic proton-sensitive dielectric, ${\mathrm{Ta}}_2{\mathrm{O}}_5,$ is used in the transistor structure in order to reduce the operational voltages. The field-effect detection of chemical species allows us to realize sensors for a variety of ions/molecules if layers with a specific functionality are added to the transistor. Organic-based sensing devices show great potential for low-cost, health-related, and environmental applications because of their very simple fabrication process, which leads to disposability.