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This special issue of Journal of Neurochemistry is devoted to the explosion of knowledge that has occurred in our understanding of the molecular and cellular basis underlying Alzheimer’s disease (AD), particularly in the twenty years that have now passed since the description of the first mutation in the amyloid precursor protein (APP) gene (Goate et al. (1991) Nature 349, 704–706). As a consequence of that discovery, the amyloid cascade hypothesis of disease progression has been at the centre of gravity of much AD research and development. Has it stood the test of time? Available treatments still remain very limited and they are palliative, rather than cures for the disease. What have we learned, where do we stand now, what new directions should we take? The amyloid cascade and its repercussions are still far from understood and do not yet recapitulate all aspects of the disease but the field is evolving rapidly with new players such as the APP intracellular domain (AICD), soluble Aβ oligomers, pyroglutamyl and other modified forms of Aβ, as well as numerous APP interacting proteins. All these recent advances, as well as new risk factors identified from genome-wide association studies that identify proteins associated with Aβ degradation or clearance, justify such a special focused issue. Hence, as editors, we have therefore asked each of the authors in this issue to present their aspect of the disease biology critically in the light of these developments.

Perhaps, the lack of success to date in translational research stems from viewing AD as a single disease rather than a group of syndromes with similar phenotypes. The genetics of early onset disease, which highlighted the APP and presenilin genes, unequivocally points to the aberrant proteolytic metabolism of APP and the generation of one or more toxic metabolites or assemblies of the amyloid β-peptide being causative. The study of this metabolic pathway has provided huge insight into completely novel areas of biology and particularly of proteolytic mechanisms, for example, membrane protein shedding, intra-membrane proteolysis, proteolytically driven nuclear signalling as well as protein and peptide degradation pathways. Late-onset disease is more likely a heterogeneous group of syndromes in which APP metabolism plays a role but is compounded by other mechanisms, including oxidative stress, calcium homoeostasis, cell death, inflammatory responses, perivascular drainage, and immune reactions, and is influenced by dietary and environmental factors.

The issue begins with a tribute by Gemma Casadesus Smith to one of the leading AD researchers over the last 20 years, Mark Smith, who sadly passed away in December last year and his loss is a huge blow to the Alzheimer community as someone who challenged orthodoxy and dogmas and was always looking for new insights into the disease pathology in a provocative but constructive manner. Mark was also a major contributor to the ISN and Journal of Neurochemistry for which he served as Reviews Editor for several years until the time of his death. Alison Goate and John Hardy then describe the impact of the discovery of the APP mutations back in 1991 both on subsequent AD research as well as on their own lives and careers. While the amyloid hypothesis may be in question in some quarters, the authors point out that clinical trials to date have generally not been satisfactory tests of the hypothesis. Hence, early detection and early intervention are critical to progress in this area.

The first half of this special issue then focuses on the processing of APP and its regulation, in which Huaxi Xu and colleagues initially provide an overview of the pathways involved and then Abraham Fisher highlights how cholinergic pathways modulate these events. For some time, the APP-cleaving enzymes referred to as secretases were activities in search of an identity, arbitrarily designated α, β, and γ and numerous proteolytic enzymes have been proposed as secretases at one time or another. The study of the constitutive non-amyloidogenic pathway of APP processing leading to the recent identification of ADAM10 as the endogenous α-secretase in primary neurons is described by Philippe Marambaud and Valérie Vingtdeux followed by Rolf Postina who focuses on the possible activation of this pathway, critically reviewing its therapeutic potential and limitations. Similarly, Robert Vassar with Patty Kandalepas, and Weihong Song with colleagues, consecutively describe the identification and regulation of the aspartic proteinase β-secretase or β-site APP-cleaving enzyme-1. Development of β-secretase inhibitors and their clinical potential is critically reviewed by Jordan Tang and colleagues. The γ-secretase is a much more complex assembly of proteins comprising the presenilins as the catalytic component together with several essential associated proteins (APH1, nicastrin, and PEN2) plus other regulatory proteins. Peter St George-Hyslop and Paul Fraser describe recent advances leading to current models of the assembly and structure of this protein complex. A major endeavour has been in designing and testing γ-secretase inhibitors and Mike Wolfe reviews the pros and cons of such compounds as therapeutics as well as strategies for selectively modulating γ-secretase activity.

The remaining sections of the special issue examine new and sometimes controversial directions in AD research, which indicate that APP exhibits a diverse metabolome and that other metabolites may contribute to its complex biology providing novel therapeutic targets. Bernadette Allinquant and Stéphanie Chasseigneaux begin by reviewing the functions of the various secreted metabolites of APP and current views on their mechanisms of action. Perhaps, the most intriguing and interesting of the APP metabolites is its intracellular domain (AICD) and its role in gene regulation. One of the co-editors of this issue (Checler) together with his colleague, Raphaëlle Pardossi-Piquard, provide a comprehensive overview of the physiology of AICD and highlight current thinking on its role in transcription and its mechanism of action. Another debated area concerns the identification of the toxic component of the Aβ peptide and Sylvain Lesné with Megan Larson describe the pathway to production of the different oligomers and their relative toxicities. Eric Klann and Tao Ma then link the Aβ peptide in its various guises to synaptic plasticity and the associated cognitive decline in AD. It is clear that Aβ itself is a physiological catabolite of APP and not just a pathological by-product of its metabolism and Colin Masters with colleagues explore how metal ions may influence Aβ biology and toxicity. The production and accumulation of Aβ is not an irreversible event since endogenous mechanisms exist for Aβ elimination, which may break down in aging and disease. Hence, manipulation of clearance pathways, especially the growing family of Aβ-degrading enzymes, provides an alternative therapeutic strategy and this field is critically reviewed by the issue co-editor (Turner) and colleagues. Finally, current outcomes from AD clinical trials, particularly immunotherapy approaches, are discussed by Bruno Vellas with colleagues and future directions in this area highlighted.

We hope that this wide-ranging and topical series of articles on the biology and pathology of AD will provide the readers with a flavour of the excitement, frustrations, and hope arising from the last 20 years of research into the disease since the identification of the first APP mutations. While there will be many more surprises in store in identifying primary and secondary disease mechanisms in AD, the APP metabolome and interactome will still dominate the scene over the next decade and we remain optimistic that these developments will lead to effective disease-modifying strategies.

Conflict of Interest

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  2. Conflict of Interest

The authors declare no conflict of interest.