Abstract Details

Title TDP43-Mediated Microglial Activation through NF-?B, AP-1 and NLRP3 Inflammasome

Topic Anterior Horn

Presentation(s) P02 - (-)

Poster/Presentation
Number 172

Objective

Background BACKGROUND: Increasing evidence supports the role of microglial activation on motoneuron death and disease progression in ALS. Transactive response DNA-binding protein 43 (TDP43) has been identified as a critical disease-related protein in ALS. However, the mechanisms whereby TDP43 contribute to neurotoxicity remain unknown.

Design/Methods DESIGN/METHODS: The effects of TDP43 on microglia were determined by using primary cultures. Microglial activation and toxicity was determined by measuring NOX2, TNF-? and IL-1? using quantitative RT-PCR and ELISA assays. Western blot was performed to detect I?B? and p65 in NF-?B pathway. Active Caspase 1 in microglia was examined using fluorescent probe FAM-YVAD-FMK.

Results RESULTS: TDP43 proteins, either wild-type (WT), 25kD C-terminal fragments, or mutant forms, were able to activate microglia by up-regulating NOX2 (major source of superoxide free radical) and cytotoxic cytokine production (TNF-? and IL-1?). PMBS, a LPS inhibitor, did not block TDP43-induced microglial activation, indicating that potential LPS contamination in the protein preparation can be excluded. TDP43 treatment resulted in activation of NF-?B pathway in microglia by decreasing I?B? protein levels, and subsequently enhancing p65 phosphorylation. The microglial response to TDP-43 was dependent on the CD14 receptor; CD14 blocking antibodies suppressed the TDP43-mediated NF-?B activation and pro-inflammatory cytokine production in microglia. AP-1 transcription factor was also involved in TNF-? and IL-1? production, which appeared to contribute to translational regulation. NLRP3 was upregluated, and active Caspase 1 was increased in TDP43-treated microglia, indicating that TDP43 also activated NLRP3 inflammasome in microglia.

Conclusions CONCLUSIONS: TDP-43 interacted with CD14 receptor and induced microglial cytotoxic activation through NF-?B/AP-1 pathways and NLRP3 inflammasome. This study suggests that efforts to block TDP43-induced microglial cytotoxicity may offer a therapeutic option for ALS.

Authors/Disclosures
Weihua Zhao, MD (Houston Methodist Neurological Institute, Houston Methodist Hospital) PRESENTER	No disclosure on file
	No disclosure on file
David R. Beers, PhD (Houston Methodist Neurological Institute)	No disclosure on file
Bing Liao, MD, MSc (Houston Methodist Hospital)	The institution of Dr. Liao has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenex. The institution of Dr. Liao has received research support from Biogen. The institution of Dr. Liao has received research support from Cabaletta Bio. The institution of Dr. Liao has received research support from Vor Bio. The institution of Dr. Liao has received research support from Allucent.
Lana Zhovtis Ryerson, MD, FAAN (Jersey Shore University Medical Center)	Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Zhovtis Ryerson has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi.
Jenny Henkel, PhD	No disclosure on file
Robert H. Baloh, MD, PhD, FAAN (Novartis Institutes for BioMedical Research)	Dr. Baloh has received personal compensation for serving as an employee of Roche. Dr. Baloh has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Acurastem. Dr. Baloh has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Irell. The institution of Dr. Baloh has received research support from NIH and CIRM.
Stanley H. Appel, MD, FAAN (Methodist Neurological Institute)	Dr. Appel has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Mitsubishi Pharma. Dr. Appel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eledon. The institution of Dr. Appel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Implicit. The institution of Dr. Appel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Coya Therapeutics. Dr. Appel has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Muscular Disease Association. Dr. Appel has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for ALS Therapy Development Institute. Dr. Appel has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for ALS Finding a Cure. Dr. Appel has stock in Stock holdings in retirement acct at Fidelity. The institution of Dr. Appel has received research support from Coya Therapeutics.

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