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Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment

Abstract

The sequential activation of Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 1 (Nlrp1) inflammasome, Caspase-1 (Casp1), and Caspase-6 (Casp6) is implicated in primary human neuron cultures and Alzheimer Disease (AD) neurodegeneration. To validate the Nlrp1-Casp1-Casp6 pathway in vivo, the APPSwedish/Indiana J20 AD transgenic mouse model was generated on either a Nlrp1, Casp1 or Casp6 null genetic background and mice were studied at 4–5 months of age. Episodic memory deficits assessed with novel object recognition were normalized by genetic ablation of Nlrp1, Casp1, or Casp6 in J20 mice. Spatial learning deficits, assessed with the Barnes Maze, were normalized in genetically ablated J20, whereas memory recall was normalized in J20/Casp1−/− and J20/Casp6−/−, and improved in J20/Nlrp1−/− mice. Hippocampal CA1 dendritic spine density of the mushroom subtype was reduced in J20, and normalized in genetically ablated J20 mice. Reduced J20 hippocampal dentate gyrus and CA3 synaptophysin levels were normalized in genetically ablated J20. Increased Iba1+-microglia in the hippocampus and cortex of J20 brains were normalized by Casp1 and Casp6 ablation and reduced by Nlrp1 ablation. Increased pro-inflammatory cytokines, TNF-α and CXCL1, in the J20 hippocampus were normalized by Nlrp1 or Casp1 genetic ablation. CXCL1 was also normalized by Casp6 genetic ablation. IFN-γ was increased and total amyloid β peptide was decreased in genetically ablated Nlrp1, Casp1 or Casp6 J20 hippocampi. We conclude that Nlrp1, Casp1, or Casp6 are implicated in AD-related cognitive impairment, inflammation, and amyloidogenesis. These results indicate that Nlrp1, Casp1, and Casp6 represent rational therapeutic targets against cognitive impairment and inflammation in AD.

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Fig. 1: Nlrp1, Casp1, or Casp6 genetic ablation prevents cognitive deficits in J20 mice.
Fig. 2: Nlrp1, Casp1, or Casp6 genetic ablation reduces activated microglia, but not astrocytes, in J20 mice.
Fig. 3: Nlrp1, Casp1, or Casp6 genetic ablation alters pro-inflammatory cytokine levels in J20 hippocampi.
Fig. 4: Nlrp1, Casp1, or Casp6 genetic ablation does not alter APP levels in J20 cortex.
Fig. 5: Nlrp1, Casp1, or Casp6 genetic ablation prevents amyloid deposition in J20 mice.
Fig. 6: Casp1, but not Nlrp1 or Casp6, genetic ablation improves survival in J20 mice.
Fig. 7: Schematic diagram summarizing the results of Nlrp1, Casp1, and Casp6 genetic ablation on J20-mediated neurodegeneration and cognitive impairment.

Data availability

The published article includes all data of individual mice tested as shown in the appropriate figures. Digital scans of full immunohistological staining and western blot membranes have been saved electronically and can be made available upon request and provision of a depository with sufficient memory to accept the files. Any additional information is available upon request.

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Acknowledgements

We acknowledge Dr. José Correa (McGill University) for his help and expertise in our statistical analyses. We thank Sébastien Harton and Dr. Julie Gervais at the IRIC at the Université de Montréal for help with breeding protocols.

Funding

This work was supported by funds from the Canadian Institutes for Health Research 2011MOP-243413-BCA-CGAG-45097 and 201610PJT-377052-PJT-CFAF-45097, Leaders Opportunity Fund, Canadian Foundation for Innovation and Jewish General Hospital Foundation to ALB.

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Conceptualization, ALB; Methodology, ALB, AN, MLF and JF; Investigation, JF, AN and MLF; Formal Analysis, JF and AN; Writing – Original Draft, ALB, JF and MLF; Writing – Review and Editing, ALB, AN, MLF and JF; Visualization, ALB, AN, and JF; Project Administration, ALB and JF; Funding Acquisition, ALB; Supervision, ALB.

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Correspondence to Andréa C. LeBlanc.

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All procedures involving animals were in accordance with the Canadian Council on Animal Care guidelines and approved by the animal care committees at Université de Montréal (protocol #20-045) and McGill University (protocol #2014-7558).

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Flores, J., Noël, A., Fillion, ML. et al. Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment. Cell Death Differ 29, 657–669 (2022). https://doi.org/10.1038/s41418-021-00881-1

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