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

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 ß 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.

ERK (MAPK) does not phosphorylate tau under physiological conditions in vivo or in vitro.

Alzheimer's disease is characterized by the deposition of intracellular aggregates of hyperphosphorylated tau protein. Tau hyperphosphorylation has been attributed in part to the deregulation of kinases and phosphatases activities. Extracellular signal regulated-kinases 1/2 (ERK1/2) were reported to be activated in the first stages of Alzheimer's disease and were proposed as a potential therapeutic target. However, although the phosphorylation of tau by ERK1/2 has been demonstrated in cell-free system, it remains controversial in vivo. Here, we showed that pharmacologic inhibition of ERK1/2 in mice and SH-SY5Y cells did not reduce basal levels of phospho-tau or hypothermia-induced tau hyperphosphorylation. We also found that activating ERK1/2 by hyperthermia did not correlate with increased tau phosphorylation. Finally, ERK1/2 was inhibited, but tau phosphorylation was not altered in Mek1-/- mice. In conclusion, these results do not support the involvement of ERK1/2 in tau phosphorylation under physiological conditions.