is presenilin dependent and is suppressed by {1S-benzyl-4R-[1S-carbamoyl-2-phenylethylcarbamoyl-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycinet-butyl ester, a potent dipeptide ␥-secretase inhibitor, builds up A1-43 and A1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of A40 appeared to lead to an increase in A43, which in turn brings an increase in A46, in a dose-dependent manner. We therefore propose an ␣-helical model in which longer A species generated by ⑀-cleavage is cleaved at every three residues in its carboxyl portion.
Accumulation of amyloid beta peptide (Abeta) in brain is a hallmark of Alzheimer's disease (AD). Inhibition of beta-site amyloid precursor protein (APP)-cleaving enzyme-1 (BACE1), the enzyme that initiates Abeta production, and other Abetalowering strategies are commonly tested in transgenic mice overexpressing mutant APP. However, sporadic AD cases, which represent the majority of AD patients, are free from the mutation and do not necessarily have overproduction of APP. In addition, the commonly used Swedish mutant APP alters APP cleavage. Therefore, testing Abeta-lowering strategies in transgenic mice may not be optimal. In this study, we investigated the impact of BACE1 inhibition in non-transgenic mice with physiologically relevant APP expression. Existing Abeta ELISAs are either relatively insensitive to mouse Abeta or not specific to full-length Abeta. A newly developed ELISA detected a significant reduction of full-length soluble Abeta 1-40 in mice with the BACE1 homozygous gene deletion or BACE1 inhibitor treatment, while the level of x-40 Abeta was moderately reduced due to detection of non-full-length Abeta and compensatory activation of alpha-secretase. These results confirmed the feasibility of Abeta reduction through BACE1 inhibition under physiological conditions. Studies using our new ELISA in non-transgenic mice provide more accurate evaluation of Abeta-reducing strategies than was previously feasible. Keywords: Alzheimer's disease, amyloid beta, beta-site amyloid precursor protein-cleaving enzyme 1, enzyme-linked immunoabsorbance assay, secretase, soluble amyloid precursor protein alpha.
We have generated synthetic peptides corresponding to various portions of human osteopontin (OPN) and have immunized rabbits and mice with these peptides to generate polyclonal and monoclonal antibodies specific to human OPN. We then generated six distinct sandwich enzyme-linked immunoabsorbent assay (ELISA) systems by using different pairs of polyclonal and monoclonal antibodies against human OPN. These systems allowed us to detect not only various isoforms and truncated forms of recombinant OPN, but also the glycosylated form of native urinary OPN. Most importantly, tumor-derived OPN was differentially detected by the six ELISA systems. The ELISA systems that we have developed will be useful for clarifying the functional roles for OPN in vivo in various physiologic and pathologic conditions.
Selective formation of an efficient ErO luminescence center in GaAs by metalorganic chemical vapor deposition under an atmosphere containing oxygenThis article investigates the structure of an Er luminescence center in GaAs by using its intra-4f-shell luminescence spectrum as an atomic probe to identify the atomic configuration. This Er center is formed in GaAs by metalorganic chemical vapor deposition with 0 codoping and the center shows a high efficiency and a sharp luminescence spectrum under above-band-gap photoexcitation. A single luminescence line in the spectrum of a GaAs:Er,O splits into more than eight lines in the spectrum of Al,,, Ga,,&s:Er,O. This drastic change due to the addition of 1% Al can be explained by assuming that, because of the high tendency of Al atoms to react with 0 atoms, the Al atoms preferentially occupy the nearest-neighbor Ga sites of two 0 atoms, both of which are coupled with the Er atom. Based on the luminescence spectra and additional experiments of Rutherford backscattering and secondary ion mass spectroscopy, we propose that the structure of the Er luminescence center under study is Er occupying the Ga sublattice with two 0 atoms most likely located at the nearest-neighbor As sites. An Er-related spectrum of GaAsa~,P,,,:Er,O can also be understood based on this model if the chemical difference of Al and P is taken into account. 4332
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