PT  - JOURNAL ARTICLE
AU  - Marco Losa
AU  - Patrick Schürch
AU  - Manfredi C. Carta
AU  - Itzel Condado Morales
AU  - Karl Frontzek
AU  - Veronika Lysenko
AU  - Asvin KK Lakkaraju
AU  - Mirzet Delic
AU  - Petra Schwarz
AU  - Gunilla T. Westermark
AU  - K. Peter Nilsson
AU  - Mario Nuvolone
AU  - Alexandre P. A. Theocharides
AU  - Simone Hornemann
AU  - Adriano Aguzzi
TI  - The ASC Protein Controls the Severity of Systemic AA Amyloidosis in Mice
AID  - 10.1101/2021.05.01.442282
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.05.01.442282
4099  - http://biorxiv.org/content/early/2021/05/02/2021.05.01.442282.short
4100  - http://biorxiv.org/content/early/2021/05/02/2021.05.01.442282.full
AB  - The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) protein is a component of inflammasomes, inflammation-mediating complexes that include Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 3 (NLRP3). ASC and NLRP3 components aggregate to form ASC specks, which can cross-seed Aβ aggregation in Alzheimer’s disease (AD). Here we asked whether ASC is involved in additional protein misfolding diseases (PMDs). AA amyloidosis is a severe complication of chronic inflammatory conditions caused by the aggregation of Serum Amyloid A (SAA) protein. Since AA and Aβ aggregates share similar biochemical properties, such as β-sheet structures, we hypothesized that ASC inflammasomes may be involved in SAA/AA recruitment, aggregation, processing and removal. We therefore investigated the role of ASC in AA amyloidosis in vivo, employing a murine AA amyloidosis model in Asc-ablated mice. We show that ASC exerts a crucial role in SAA recruitment in the presence of AA fibrils, that splenic AA amyloid load was decreased in Asc-/- mice, that the presence of ASC accelerates SAA fibril formation and that ASC is important for SAA-activated phagocytosis of macrophages. We conclude that ASC modulates both SAA serum levels and the severity of AA amyloidosis in mice. ASC may represent a therapeutic target in AA as well as other amyloidosis entities.Competing Interest StatementThe authors have declared no competing interest.