TY  - JOUR
AU  - Friker, Lea L.
AU  - Scheiblich, Hannah
AU  - Hochheiser, Inga V.
AU  - Brinkschulte, Rebecca
AU  - Riedel, Dietmar
AU  - Latz, Eicke
AU  - Geyer, Matthias
AU  - Heneka, Michael T.
TI  - β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia
JO  - Cell reports
VL  - 30
IS  - 11
SN  - 2211-1247
CY  - [New York, NY]
PB  - Elsevier
M1  - DZNE-2020-01240
SP  - 3743 - 3754.e6
PY  - 2020
AB  - Alzheimer’s disease is the world’s most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by β-amyloid (Aβ) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Aβ, we investigate the propagation of ASC between primary microglia and the effects of ASC-Aβ composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Aβ composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free functional ASC and inducing a feedforward stimulating vicious cycle. Clustering around ASC fibrils also compromises clearance of Aβ by microglia. Together, these data enable a closer look at the turning point from acute to chronic Aβ-related neuroinflammation through formation of ASC-Aβ composites.
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloid beta-Peptides: toxicity
KW  - Amyloid beta-Peptides: ultrastructure
KW  - Animals
KW  - CARD Signaling Adaptor Proteins: metabolism
KW  - Caspase 1: metabolism
KW  - Cells, Cultured
KW  - Humans
KW  - Inflammasomes: metabolism
KW  - Interleukin-1beta: metabolism
KW  - Mice, Inbred C57BL
KW  - Microglia: drug effects
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Models, Biological
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Proteolysis: drug effects
KW  - Pyroptosis: drug effects
KW  - Signal Transduction: drug effects
KW  - Toll-Like Receptor 2: metabolism
KW  - Toll-Like Receptor 4: metabolism
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC8729885
C6  - pmid:32187546
DO  - DOI:10.1016/j.celrep.2020.02.025
UR  - https://pub.dzne.de/record/151661
ER  -