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Notes: Abstract Systems that generate spike outputs in response to continuous inputs abound in neurophysiology. The study of their dynamics with the use of systems analysis methods has been complicated by the difference in modality of the input and output signals. When the problem is placed in the framework of Wiener's theory in discrete time, an infinite functional series is required for the formal representation of the input-output relation. This has given rise to the belief that a large number of Wiener functionals is needed in practice before a model of reasonable accuracy can be obtained. In this paper, we introduce the concept of minimum-order Wiener models for spike-output systems, and we show that a low-order Wiener model is adequate in many cases for predicting fully the timing of the output spikes.

Notes: The amyloid β-protein (Aβ) is a proteolytic fragment of the β-amyloid precursor protein (βAPP). We previously reported the constitutive secretion of Aβ peptides from a variety of cells expressing βAPP under normal culture conditions. These endogenously produced Aβpeptides have heterogeneous N-and C-termini that vary as a function of βAPP missense mutations. Treatment of Aβ-secreting cells with agents that alter intravesicular pH showed that an acidic compartment is required for proper Aβ generation. One such compartment appears to be the endosome. Immunolabeling of cell-surface βAPP in living neurons and non-neuronal cells directly demonstrated the endocytosis of the protein and its rapid recycling (within 5–10 minutes) to the cell surface, as well as the trafficking of some βAPP to lysosomes. Expression of βAPP with various deletions of the cytoplasmic domain, including the NPTY motif, leads to decreased internalization and an associated decrease in the production of Aβ peptides that begin at the usual asp1 start site. These and other data suggest that Aβ production begins with cleavage of βAPP by a still unknown protease(s) (β-secretase[s] at the met-asp bond preceding the Aβ N-terminus and that this occurs in part in early endosomes. To characterize the substrate requirements of β-secretase, βAPP was mutagenized by placing stop codons within or at the end of the transmembrane domain or substituting other amino acids for the wild-type met and asp at the P1 and P1' positions. These experiments showed that proper β-secretase cleavage requires the precursor to be membrane-anchored and is highly sequence specific; most substitutions at met or asp substantially decrease Aβ production. Analogous mutagenesis experiments around the Aβ C-terminus revealed that the unknown protease(s) cleaving here (“γ-secretase[s]”) does not show such specificity. Cells secreting Aβ may also be useful for examining the critical issue of the aggregation of Aβ into its neurotoxic polymeric form under physiological conditions. In this regard, we have found that AβAPP-expressing CHO cells show aggregation of 〈inlineGraphic alt="geqslant R: gt-or-equal, slanted" extraInfo="nonStandardEntity" href="urn:x-wiley:00778923:NYAS57:ges" location="ges.gif"/〉 10-20% of their secreted Aβ peptides into SDS-stable dimers, trimers and sometimes tetramers under normal culture conditions. The identity of these small multimers was confirmed by extensive immunochemical characterization and radiosequencing. They are present at  100-500 pM levels in conditioned medium of CHO transfectants. Using this endogenous Aβ aggregating system, we have begun to examine variables that influence aggregation and compounds which may retard it. In conclusion, studies of the regulation of Aβ production and aggregation in cell culture can provide information under physiological conditions that can complement analyses of these processes in vivo.

Notes: Abstract In a previous paper (Marmarelis et al. 1986) we presented the concept of minimum-order Wiener (MOW) modeling of continuous-input/spike-output (CISO) systems. The associated MOW methodology aims at obtaining low-order Wiener models for CISO systems of practical interest. The assertion was made that many neurophysiological systems that fall in this class can be studied effectively by the use of this method. We have chosen a sensory system to demonstrate the efficacy of the method with actual experimental data. The response of retinal ganglion cells to spatiotemporal visual stimuli was studied with this approach and a second-order MOW model was obtained. The results appear to corroborate the adequacy of this model in terms of predicting the timing of the output spikes.

Notes: [Auszug] To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid β-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid β–protein (Aβ) ending at Aβ42(43) in vivo, we performed a ...