title: AChE and the amyloid precursor protein (APP) - Cross-talk in Alzheimer's disease.
abstract: The amyloid precursor protein (APP) and acetylcholinesterase (AChE) are multi-faceted proteins with a wide range of vital functions, both crucially linked with the pathogenesis of Alzheimer's disease (AD). APP is the precursor of the Aβ peptide, the pathological agent in AD, while AChE is linked to its pathogenesis either by increasing cholinergic deficit or exacerbating Aβ fibril formation and toxicity. As such, both proteins are the main targets in AD therapeutics with AChE inhibitors being currently the only clinically available AD drugs. In our studies we have demonstrated an important inter-relation in functioning of these proteins. Both can be released from the cell membrane and we have shown that AChE shedding involves a metalloproteinase-mediated mechanism which, like the α-secretase dependent cleavage of APP, is stimulated by cholinergic agonists. Overexpression of the neuronal specific isoform APP695 in neuronal cells substantially decreased levels of the AChE mRNA, protein and catalytic activity accompanied by a similar decrease in mRNA levels of the AChE membrane anchor, PRiMA (proline rich membrane anchor). We further established that this regulation does not involve APP processing and its intracellular domain (AICD) but requires the E1 region of APP, specifically its copper-binding domain. On the contrary, siRNA knock-down of APP in cholinergic SN56 cells resulted in a significant upregulation of AChE mRNA levels. Hence APP may influence AChE physiology while released AChE may regulate amyloidogenesis through multiple mechanisms suggesting novel therapeutic targets.
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK; Sechenov Institute of Evolutionary Physiology and Biochemistry of Russian Academy of Sciences (RAS), 44 Thorez av, Saint Petersburg, 194223, Russia. Electronic address: n.n.nalivaeva@leeds.ac.uk.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Nalivaeva
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Electronic address: a.j.turner@leeds.ac.uk.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Turner
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor; D020033:Protein Isoforms; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Amyloid precursor protein (APP); Butyrylcholinesterase