β-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia

Lea L Friker,Hannah Scheiblich,Inga V Hochheiser,Rebecca Brinkschulte,Dietmar Riedel,Eicke Latz,Matthias Geyer,Michael T Heneka

doi:10.1016/j.celrep.2020.02.025

Abstract

SUMMARYAlzheimer’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.

Highlights

Alzheimer’s disease (AD) is the most common dementing illness, characterized by progressive memory decline and cognitive dysfunction (Zverova, 2019)
NLRP3 inflammasome activation relies on two signals: transcriptional upregulation of inflammasome components via the transcription factor nuclear factor kB (NF-kB) (Kawai and Akira, 2010) and a second signal generated by danger-associated molecular patterns (DAMPs)-induced ion fluxes, mitochondrial reactive oxygen species (ROS) production, or lysosomal destabilization, which, in turn, leads to assembly and activation of the inflammasome (Yang et al, 2019)
Our findings indicate that Ab clustering around ASC fibrils boosts its toxicity in microglia

Summary

Introduction

Alzheimer’s disease (AD) is the most common dementing illness, characterized by progressive memory decline and cognitive dysfunction (Zverova , 2019). The balance of Ab and tau deposition and clearance is maintained by brain-resident microglia. As resident immune effector cells of the CNS, microglia play a crucial role in mediating brain homeostasis and the innate immune response against a wide range of pathogenic factors (Clayton et al, 2017; Hanisch and Kettenmann, 2007). Microglia sense a variety of microbial molecules called pathogen-associated molecular patterns (PAMPs) and host-derived danger-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). PRR ligation fuels signaling transduction pathways that induce an inflammatory response and lead to clearance of debris by phagocytosis (Heneka et al, 2014). NLRP3 inflammasome activation relies on two signals: transcriptional upregulation of inflammasome components via the transcription factor nuclear factor kB (NF-kB) (Kawai and Akira, 2010) and a second signal generated by DAMP-induced ion fluxes, mitochondrial reactive oxygen species (ROS) production, or lysosomal destabilization, which, in turn, leads to assembly and activation of the inflammasome (Yang et al, 2019)

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