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The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis The University of Manchester Research A Greek Tragedy: the Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis DOI: 10.1074/jbc.R116.746032 Document Version Accepted author manuscript Link to publication record in Manchester Research Explorer Citation for published version (APA): Andrew, R. J., Kellett, K., Thinakaran, G., & Hooper, N. (2016). A Greek Tragedy: the Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis. Journal of Biological Chemistry, 291, 19235-19244. https://doi.org/10.1074/jbc.R116.746032 Published in: Journal of Biological Chemistry Citing this paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. General rights Copyright and moral rights for the publications made accessible in the Research Explorer are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Takedown policy If you believe that this document breaches copyright please refer to the University of Manchester’s Takedown Procedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providing relevant details, so we can investigate your claim. Download date:03. Oct. 2021 A Greek Tragedy: the Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis Robert J. Andrew1*, Katherine A. B. Kellett2, Gopal Thinakaran1 & Nigel M. Hooper2* 1Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA 2Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK Running title: Amyloid precursor protein proteolysis *To whom correspondence should be addressed: [email protected] tel. +1 773 834 3771 or [email protected] tel. +44 161 306 5765. Keywords: Alzheimer disease, amyloid, proteolysis, secretase, BACE1, ADAM10, presenilin. Abbreviations: Aβ, amyloid-β; AD, Alzheimer disease; ADAM, a disintegrin and metalloprotease; AEP, asparagine endopeptidase; AICD, APP intracellular domain; APP, amyloid precursor protein; APLP, amyloid precursor-like protein; BACE1, β-site APP cleaving enzyme 1; CSF, cerebrospinal fluid; CTF, C-terminal fragment; PS, presenilin; sAPP, soluble amyloid precursor protein. __________________________________________________________________________________ Abstract identification of the Aβ peptide 25 years ago Proteolysis of the amyloid precursor protein has not yet led to the advent of a viable (APP) liberates various fragments including therapeutic strategy which can slow or halt the the proposed initiator of Alzheimer disease progression of AD. Recent studies have associated dysfunctions, amyloid-β. However, revealed new complexities in the proteolytic recent evidence suggests the accepted view of processing of APP, including the identification APP proteolysis by the canonical α-, β- and γ- of novel secretases which generate APP secretases is simplistic, with the discovery of a metabolites that accumulate in the brains of number of novel APP secretases (including δ- AD patients and may contribute to the synaptic and η-secretases, alternative β-secretases) and dysfunction observed in the disease. In additional metabolites, some of which may addition, numerous proteins are being also cause synaptic dysfunction. Furthermore, identified that interact with APP, modulating various proteins have been identified that its proteolysis and Aβ production. These new interact with APP and modulate its cleavage APP secretases and metabolites, along with the by the secretases. Here, we give an overview APP interactors, may present novel therapeutic of the increasingly complex picture of APP targets, that are independent of direct proteolysis. modulation of the canonical secretases, and _____________________________________ which will need to be considered when evaluating the results from current Aβ-directed Currently over 46 million people worldwide therapies. In this minireview, we summarise are living with dementia (www.alz.co.uk) with the recent developments in APP proteolysis Alzheimer disease (AD) representing the most focusing on the novel secretases, APP common form of dementia. In AD, the interactors and APP metabolites that are amyloid cascade hypothesis posits that impacting on our understanding of both APP amyloid-β (Aβ), produced through the biology and the neurodegenerative disease sequential proteolytic cleavage of the amyloid process. precursor protein (APP) by the β- and γ- secretases, is a key molecule in initiating and The canonical α-, β- and γ-secretases and propagating disease pathology including APP fragments neurofibrillary tangle formation, neuronal cell The generally accepted model of APP loss, aberrant synaptic activity, and brain proteolysis is that APP is processed by one of atrophy that lead to the clinically recognised two distinct proteolytic pathways (Fig. 1A). In symptoms of dementia (1). However, the amyloidogenic pathway, β-secretase, the β- 1 site APP cleaving enzyme 1 (BACE1), cleaves superresolution microscopy. The complex APP within the ectodomain and liberates a between the two secretases was stabilised by soluble proteolytic fragment, termed soluble members of the tetraspanin family of scaffold APPβ (sAPPβ), primarily in the endosomal proteins (namely tetraspanin 12 and 17). system from the transmembrane APP Limited data also indicated a physical holoprotein (2). The remaining C-terminal interaction between BACE1 and γ-secretase, membrane-bound APP fragment, CTFβ, is albeit in a complex distinct from the subsequently cleaved by the presenilin (PS)- ADAM10-γ-secretase complex (9). This containing γ-secretase multi-subunit complex comprehensive biochemical study suggests to liberate the Aβ peptide and the APP that cells possess large multiprotease intracellular domain (AICD) (Fig. 1A). γ- complexes capable of sequentially and secretase cleaves CTFβ at several sites in the efficiently processing transmembrane transmembrane domain, ‘trimming’ the Aβ substrates such as APP through a spatially peptide from the initial ε-cleavage sites to coordinated regulated proteolytic mechanism produce shorter, and relatively benign, Aβ (9). This raises the interesting question as to species (Fig. 2) (3). However, inefficient whether these multiprotease complexes could trimming of the Aβ peptide at its C-terminus be targeted to modulate selectively APP results in the release of longer aggregation- processing in the amyloidogenic pathway. prone Aβ species such as Aβ42, which are Whether there is a reciprocal relationship central to the production of the neurotoxic between the amyloidogenic and non- oligomeric Aβ assemblies (4,5). In the non- amyloidogenic APP processing pathways has amyloidogenic pathway, α-secretase, members remained a contentious issue, possibly as a of the “a disintegrin and metalloprotease” result of differences in the model systems (ADAM) family, mainly ADAM10, cleaves being examined (10). In monkeys, BACE1 APP at the cell surface within the Aβ domain inhibition decreased sAPPβ and Aβ in liberating soluble APPα (sAPPα) and leaving cerebrospinal fluid (CSF) and increased an alternative membrane-bound C-terminal sAPPα as measured by ELISA but there was fragment, CTFα. CTFα can also be no change in labelled sAPPα kinetics, subsequently proteolytically processed by γ- suggesting BACE1 inhibition may not boost α- secretase to liberate an N-terminally truncated secretase processing of APP to the same version of the Aβ peptide referred to as p3 and degree (11). In human induced pluripotent the AICD (Fig. 1A). The AICD has a role as a stem cell-derived neurons inhibition of nuclear transcription factor regulating the BACE1 reduced sAPPβ and Aβ and expression of various genes, including that of reciprocally increased sAPPα (12), while the Aβ-degrading neprilysin (6-8). Although inhibition of γ-secretase resulted in an increase the AICD produced via either the in sAPPα and a decrease in sAPPβ (9). This amyloidogenic or non-amyloidogenic latter result suggests a level of feedback within pathways have the same peptide sequence, the ADAM10-γ-secretase complex (9). they appear to be functionally distinct. The Activating α-secretase has been suggested as a AICD produced following β-secretase potential therapeutic approach for reducing Aβ cleavage is transported to the nucleus and production although the evidence for this from binds to the neprilysin gene promoter, whereas in vivo studies is somewhat mixed (13,14). For that produced following α-secretase cleavage example, moderate neuronal overexpression of is rapidly degraded in the cytosol by insulin- ADAM10 in APPV717I transgenic mice degrading enzyme (6). increased the secretion of sAPPα, reduced the The established view is that these formation of Aβ peptides, and prevented their sequential cleavages of APP occur through deposition in plaques (15). While in APP/PS-1 separate enzyme-substrate interactions which transgenic mice the intracerebral injection of are temporally and spatially separated. the vitamin A analogue acitretin, which However, recent evidence indicates that stimulates ADAM10 promoter activity, led to ADAM10 and γ-secretase physically interact a reduction of Aβ40 and Aβ42 (16). However, and
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