Journal Article

FZJ-2019-02163

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β1–42-stimulated murine astrocytes

Ebrahimi, T. ; Rust, M. ; Kaiser, S. N. ; Slowik, A. ; Beyer, C. ; Koczulla, A. R. ; Schulz, J. B.FZJ* ; Habib, P. ; Bach, J. P. (Corresponding author)

2018
BioMed Central London

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Please use a persistent id in citations: http://hdl.handle.net/2128/21917  doi:10.1186/s12974-018-1319-x

Abstract: BackgroundNeuroinflammation has an essential impact on the pathogenesis and progression of Alzheimer’s disease (AD). Mostly mediated by microglia and astrocytes, inflammatory processes lead to degeneration of neuronal cells. The NLRP3-inflammasome (NOD-like receptor family, pyrin domain containing 3) is a key component of the innate immune system and its activation results in secretion of the proinflammatory effectors interleukin-1β (IL-1β) and interleukin-18 (IL-18). Under physiological conditions, cytosolic NLRP3-inflammsome is maintained in an inactive form, not able to oligomerize. Amyloid β1–42 (Aβ1–42) triggers activation of NLRP3-inflammasome in microglia and astrocytes, inducing oligomerization and thus recruitment of proinflammatory proteases. NLRP3-inflammasome was found highly expressed in human brains diagnosed with AD. Moreover, NLRP3-deficient mice carrying mutations associated with familial AD were partially protected from deficits associated with AD.The endogenous protease inhibitor α1-antitrypsin (A1AT) is known for its anti-inflammatory and anti-apoptotic properties and thus could serve as therapeutic agent for NLRP3-inhibition. A1AT protects neurons from glutamate-induced toxicity and reduces Aβ1–42-induced inflammation in microglial cells. In this study, we investigated the effect of Aβ1–42-induced NLRP3-inflammasome upregulation in primary murine astrocytes and its regulation by A1AT.MethodsPrimary cortical astrocytes from BALB/c mice were stimulated with Aβ1–42 and treated with A1AT. Regulation of NLRP3-inflammasome was examined by immunocytochemistry, PCR, western blot and ELISA. Our studies included an inhibitor of NLRP3 to elucidate direct interactions between A1AT and NLRP3-inflammasome components.ResultsOur study revealed that A1AT reduces Aβ1–42-dependent upregulation of NLRP3 at the mRNA and protein levels. Furthermore, A1AT time-dependently mitigated the expression of caspase 1 and its cleavage product IL-1β in Aβ1–42-stimulated astrocytes.ConclusionWe conclude that Aβ1–42-stimulation results in an upregulation of NLRP3, caspase 1, and its cleavage products in astrocytes. A1AT time-dependently hampers neuroinflammation by downregulation of Aβ1–42-mediated NLRP3-inflammasome expression and thus may serve as a pharmaceutical opportunity for the treatment of Alzheimer’s disease.

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Contributing Institute(s):

1. Jara-Institut Quantum Information (INM-11)

Research Program(s):

1. 572 - (Dys-)function and Plasticity (POF3-572) (POF3-572)

Appears in the scientific report 2019

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