K-Ar age determinations, mainly whole rock, with some corroboration from mineral separates, are presented for lava flows, domes, minor intrusives and blocks in tuffs from 95 localities in the Lesser Antilles. Together with the much smaller number of previously published data, these show a distinction between a range 38-10 million years (Ma) in the outer arc (Limestone Caribbees) and less than 7.7 Ma in the inner arc (Volcanic Caribbees). From southern Martinique southwards, the two arcs are superposed, and the whole range is fragmentarily represented. The observed age ranges in the outer and inner arcs fit between discontinuities in sea floor spreading in the North Atlantic at ca. 38 and ca. 9 Ma and a causal connection between spreading change and relocation of arc volcanicity is suggested. Palaeomagnetic directions at 108 localities in ten of the islands fall into normal ( N = 56, k = 13.8, D = 359°, I = + 22°, pole position 229° E, 89° N with drjr = 3°, d X = 6°) and reversed groups ( N = 41, k = 14.1, D = 178°, I = -22°, pole position 18° E, 88° S with d xjr = 3°, dx = 6°) plus six sites of intermediate polarity and five sites indeterminate. The mean dipole axis is within 2° of the present rotation axis and is likely to be identical with it with a probability of 99%. The data are generally in accord with the established geomagnetic polarity time scale, but there is some suggestion of a normal polarity event at ca. 1.18 Ma within the Matuyama Reversed Epoch. The palaeomagnetic data relate mainly to be past 10 Ma and suggest that within that time the Lesser Antilles have not changed their latitude or geographic orientation, and that the geomagnetic field has averaged that of a centred axial dipole. The few older palaeomagnetic data are consistent with these same conclusions (though with less certainty) back to ca. 20 Ma ago. There is no evidence for oroclinal bending of the arc since then.

Generation of the amyloid peptide through proteolytic processing of the amyloid precursor protein by ␤-and ␥-secretases is central to the etiology of Alzheimer's disease. ␤-secretase, known more widely as the ␤-site amyloid precursor protein cleaving enzyme 1 (BACE1), has been identified as a transmembrane aspartic proteinase, and its ectodomain has been reported to be cleaved and secreted from cells in a soluble form. The extracellular domains of many diverse proteins are known to be cleaved and secreted from cells by a process known as ectodomain shedding. Here we confirm that the ectodomain of BACE1 is secreted from cells and that this processing is up-regulated by agents that activate protein kinase C. A metalloproteinase is involved in the cleavage of BACE1 as hydroxamic acid-based metalloproteinase inhibitors abolish the release of shed BACE1. Using potent and selective inhibitors, we demonstrate that ADAM10 is a strong candidate for the BACE1 sheddase. In addition, we show that the BACE1 sheddase is distinct from ␣-secretase and, importantly, that inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the ␤-site.The extracellular domains of a diverse range of cell proteins are cleaved and released from cells in a soluble form by a process known as ectodomain shedding. Membrane-anchored proteins that undergo such cleavage include cytokines, cytokine receptors, growth factors, growth factor receptors, cell adhesion molecules (1), and proteins of unknown function, including the amyloid precursor protein (APP) 1 (2). The ectodomain shedding of these proteins exhibits three main characteristics. First, shedding is enhanced by agents, such as phorbol esters, that activate protein kinase C (3, 4). Second, shedding is sensitive to hydroxamic acid-based metalloproteinase inhibitors (1, 5, 6). Third, shedding appears to occur at or near the cell surface (7-9).A number of enzymes are known to be involved in the ectodomain shedding of cell surface proteins. The first sheddase to be identified was the tumor necrosis factor ␣ (TNF␣)-converting enzyme (TACE) (10, 11), which cleaves the ectodomain of pro-TNF␣. TACE, also known as ADAM17, is a member of the a disintegrin and metalloproteinase (ADAM) family of metalloproteinases (12, 13) and has been reported to mediate ectodomain shedding of other proteins such as L-selectin (14), interleukin-1 receptor (15), and APP by cleavage at the ␣-site (16, 17). In addition to TACE, two other members of the ADAM family of metalloproteinases, ADAM9 and ADAM10, have also been proposed as ␣-secretases (18, 19). ADAM9 and ADAM10, in common with other sheddase activities, exhibit regulation by protein kinase C and inhibition by hydroxamic acid-based metalloproteinase inhibitors.Proteolytic processing of the APP appears to be central to the etiology of Alzheimer's disease (AD). Cleavage of APP by ␤-and ␥-secretases generates the amyloidogenic peptide A␤, which aggregates to form senile plaque (20). In an alternative nonamyloidogenic pathway, cleavage of A...

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Multiple proteins are proteolytically shed from the membrane, including the amyloid precursor protein (APP) involved in Alzheimer's disease, the blood pressure regulating angiotensin converting enzyme (ACE), the low affinity IgE receptor CD23, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). The inhibitory effect of a range of hydroxamic acid-based compounds on the secretases involved in cleaving and releasing these four proteins has been examined to build up a structure-activity relationship. Compounds have been identified that can discriminate between TNF-alpha convertase and the other three secretases (compound 15), between the shedding of CD23 and the shedding of APP and ACE (compound 21), and between the secretases and matrix metalloproteinase-1 (compound 22). The structure-activity relationship for the APP alpha-secretase and the ACE secretase were remarkably similar, and both secretases were activated in whole cell systems by the serine proteinase inhibitor 3,4-dichloroisocoumarin. The basal and carbachol-stimulated shedding of APP and ACE from human SH-SY5Y neuroblastoma cells could not be differentiated by any of the hydroxamate compounds, implying that the same or very similar activities are involved in the constitutive and regulated shedding of these two proteins. By utilizing a key discriminatory compound (compound 15) that potently inhibits TNF-alpha convertase but not alpha-secretase, we show that TNF-alpha convertase is not involved in the regulated shedding of APP from human neuronal cells. The compounds reported here will be useful in future studies aimed at identifying and validating candidate secretases.

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