Blocking Inflammasome Activation Caused by β‑Amyloid Peptide (Aβ) and Islet Amyloid Polypeptide (IAPP) through an IAPP Mimic

• Published in: ACS chemical neuroscience Vol. 10; no. 8; pp. 3703 - 3717
• Main Authors: Aftabizadeh, Maryam, Tatarek-Nossol, Marianna, Andreetto, Erika, El Bounkari, Omar, Kipp, Markus, Beyer, Cordian, Latz, Eicke, Bernhagen, Jürgen, Kapurniotu, Aphrodite
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.08.2019
• Subjects: inflammasome activation; amyloid inhibitor; type 2 diabetes; β-amyloid peptide; Alzheimer’s disease; Islet amyloid polypeptide
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.9b00260

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 β-amyloid peptide (Aβ) 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-1β (IL-1β), a key proinflammatory cytokine in both diseases. Here we show that the inflammatory processes mediated by Aβ and IAPP aggregates in microglial cells and macrophages are blocked by IAPP-GI, a nonamyloidogenic IAPP mimic, which forms high-affinity soluble and nonfibrillar hetero-oligomers with both polypeptides. In contrast to fibrillar Aβ aggregates, nonfibrillar Aβ/IAPP-GI or Aβ/IAPP hetero-oligomers become rapidly internalized by microglial cells and targeted to lysosomes where Aβ 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/Aβ cross-amyloid interaction and suggest that conversion of Aβ 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.