Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to -Amyloid peptide accumulation

-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by -Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, -Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the -Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing -Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced -Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that -Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.