Heterologous Amyloid Seeding: Revisiting the Role of Acetylcholinesterase in Alzheimer's Disease

摘要: Neurodegenerative diseases associated with abnormal protein folding and ordered aggregation require an initial trigger which may be infectious, inherited, post-inflammatory or idiopathic. Proteolytic cleavage to generate vulnerable precursors, such as amyloid-β peptide (Aβ) production via β γ secretases in Alzheimer's Disease (AD), is one trigger, but the proteolytic removal of these fragments also aetiologically important. The levels Aβ central nervous system are regulated by several catabolic proteases, including insulysin (IDE) neprilysin (NEP). known association human acetylcholinesterase (hAChE) pathological aggregates AD together its ability increase fibrilization prompted us search for triggers that could enhance this process. hAChE C-terminal domain (T40, AChE575-614) exposed amphiphilic α-helix involved enzyme oligomerisation, it contains a conformational switch region (CSR) high propensity conversion non-native (hidden) β-strand, property amyloidogenicity. A synthetic (AChE586-599) encompassing CSR shares homology forms β-sheet amyloid fibrils. We investigated influence IDE NEP proteolysis on formation degradation relevant species. By combining reverse-phase HPLC mass spectrometry, we established digestion profiles T40 versus AChE586-599, Aβ, differed. Moreover, triggered from α- β-structures, resulting surfactant species self-assembled into fibril precursors (oligomers). Crucially, significantly increased both seeding energetically unfavorable nuclei enhancing rate elongation. Hence, results offer explanation observations implicate extent deposition brain. Furthermore, process heterologous fragment another represent previously underestimated implying abundance major amyloidogenic (Aβ AD, example) not only important factor neurodegeneration.