Blocking Inflammasome Activation Caused by beta-Amyloid Peptide (A beta) and Islet Amyloid Polypeptide (IAPP) through an IAPP Mimic

Aftabizadeh, Maryam; Tatarek-Nossol, Marianna; Andreetto, Erika; El Bounkari, Omar; Kipp, Markus; Beyer, Cordian; Latz, Eicke; Bernhagen, Jürgen und Kapurniotu, Aphrodite (2019): Blocking Inflammasome Activation Caused by beta-Amyloid Peptide (A beta) and Islet Amyloid Polypeptide (IAPP) through an IAPP Mimic. In: ACS Chemical Neuroscience, Bd. 10, Nr. 8: S. 3703-3717

Abstract

Inflammation in the brain and pancreas is linked to cell degeneration and pathogenesis of both Alzheimer's disease (AD) and type 2 diabetes (T2D). Inflammatory cascades in both tissues are triggered by the uptake of beta-amyloid peptide (A beta) or islet amyloid polypeptide (IAPP) aggregates by microglial cells (AD) or macrophages (T2D) and their insufficient lysosomal degradation. This results in lysosomal damage, caspase-1/NLRP3 inflammasome activation and release of interleukin-1 beta (IL-1 beta), a key proinflammatory cytokine in both diseases. Here we show that the inflammatory processes mediated by A beta and IAPP aggregates in microglial cells and macrophages are blocked by IAPP-GI, a nonamyloidogenic IAPP mimic, which forms high-affinity soluble and nonfibrillar heterooligomers with both polypeptides. In contrast to fibrillar A beta aggregates, nonfibrillar beta/IAPP-GI or A beta/IAPP hetero-oligomers become rapidly internalized by microglial cells and targeted to lysosomes where A beta is fully degraded. Internalization occurs via IAPP receptor-mediated endocytosis. Moreover, in contrast to IAPP aggregates, IAPP/IAPP-GI hetero-oligomers become rapidly internalized and degraded in the lysosomal compartments of macrophages. Our findings uncover a previously unknown function for the IAPP/A beta cross-amyloid interaction and suggest that conversion of A beta or IAPP into lysosome-targeted and easily degradable hetero-oligomers by heteroassociation with IAPP mimics could become a promising approach to specifically prevent amyloid-mediated inflammation in AD, T2D, or both diseases.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1948-7193
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198