Editorial [ Production and Fate of Amyloid Peptides: Recent Advances and Perspectives ]

Alois Alzheimer's described his seminal observation more than one hundred years ago. Yet, the main component of one of the principal cerebral lesions, the senile plaque, was only identified in 1984 by Glenner and Wong. This discovery now appears as a temporal frontier between important initial research that was mainly descriptive in nature and a new modern area in which the biology of the disease was investigated and the quest for causal determinants was initiated. An important step towards the understanding of the etiology of Alzheimer's disease (AD) was achieved when the genes harboring autosomal dominant mutations were identified as those encoding the β-amyloid precursor protein (APP) and presenilins. Thus, even if these mutations overall account for a low percentage of AD cases, they proved extremely useful to delineate some of the perturbations occurring in AD brain. Particularly interesting was the observation that although APP and presenilins are distinct entities, mutations on these proteins all lead to a modification of APP processing and altered production of amyloid-β (Aβ) peptides. Therefore, Aβ (or more likely a set of Aβ peptides) can be seen as a common molecular denominator for various “types” of AD [1]. Does it mean that Aβ is, stricto sensu, the only etiological determinant of the disease? Likely not, and we all agree that environmental and risk factors among others could drastically influence the course of the disease, as supported by the fact that patients harboring identical mutations on presenilins could develop the disease with a strikingly variable age of onset. On the other hand, it is hard to unquestionably deem that Aβ-like peptides (including their various biophysical states) have nothing to do with the neurodegenerative process. However, even if the majority is not always right [in science], the fact remains that the so-called amyloid cascade postulating a key role of Aβ in AD pathogenesis is one of the main hypothesis studied worldwide. On the whole, much attention has been paid to the mechanisms by which Aβ peptides are produced and cleared off. Hence, some of the molecular actors were identified a dozen or so years ago and an immense amount of information has been gathered. However, in this regard it is again remarkable that some of the data are not consensual and sometimes hardly discussed. This explains why a special issue of the Current Alzheimer's Research has been dedicated to the various catalytic events and putative enzymes involved in the proteolytic conversion of APP. In the field, there are the “good” and the “bad”. We can identify the bad as the enzymes that produce Aβ peptides: β- and ??-secretases. It is obviously somewhat caricatural because, Aβ remains a catabolic product of physiological APP processing and potential “toxic” or “deleterious” effects are drastically linked to the concentration of Aβ monomers, the biophysical state of Aβ (fibrils, protofibrils, aggregates) and the nature and ratio of Aβ-like peptides (Aβ40/42, Nterminally truncated, C-terminally extended). It stands that aggregation processes or secondary cleavages yielding Aβ- like species harboring enhanced toxicity remains dependent upon the initial cleavages yielding “genuine” Aβ. As a corollary, the proteases involved in these cleavages are of great importance. The enzyme β-secretase liberates the N-terminal moiety of Aβ and has been consensually identified as an aspartyl protease referred to as BACE1 (β-site APP cleaving enzyme), memapsin 2 or ASP2 by several independent groups. Cole and Vassar with Tang and colleagues, two of the discoverers of the enzyme, describe here (pp. 100-131) the biology of β-secretase and survey the recent potential pharmacological blockers of the enzyme as putative therapeutic probes. γ-secretase is one of the stars in the field. Thus, the enzyme is particularly important as it conditions the nature of the C-terminal part of Aβ peptides, which drives their toxic potential. There likely exist several γ-secretases, dependent or independent of presenilins, but the former has been the center of a significant amount of data leading to the discovery of a high molecular weight complex, the biologically active structure of which still remains debated. The biology of the complex, i.e its assembly and proteolytic maturation is currently a rapidly “moving” field. Therefore, the state of the art description of the γ-secretase complex (Dries and Yu, pp. 132-146), the revisited survey on presenilin structure and function (Steiner, pp. 147-157) and the late developments concerning the design of presenilin-directed γ-secretase inhibitors (Wolfe, pp. 158-164) are included in this issue. Of particular interest, (Kametani, pp. 165-171) describe recent advances concerning an additional “epsilon” cleavage site on APP that has been the center of many recent studies, while Xia overviews (pp. 172-178) the data available on presenilinase, an activity that harbors the potential of cleaving presenilins, thereby yielding the catalytically active γ- secretase complex.