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

Abstract

β-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 β-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, β-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 β-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing β-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced β-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 β-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.

Autophagy and cardiac aging

“…Deletion of NLRP3 leads to higher PINK1 expression leading to elimination of damaged mitochondria and suppression of apoptosis under stress conditions, suggesting an inhibitory role of the NLRP3 inflammasome in PINK1-dependent mitophagy [122]. Deletion of caspase-1, the effector molecule in the inflammasome, increases autophagy and provides cellular protection in macrophages and in neuronal cells [123,124]. Furthermore, NLRP3 activation triggers mitochondrial damage through caspase-1 activation and this is further amplified by inhibition of mitophagy mediated by Parkin cleavage by caspase-1 in macrophages [125].…”

A 3′UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice

“…LC3-associated phagocytosis has been connected to immune regulation and inflammation 38 . LC3 has also been implicated in the clearance mechanisms involved in Aβ removal and neurodegeneration in 5XFAD mice 39 . To examine whether alterations in LC3 related autophagy are involved in the decreased amyloid deposition in 5XFAD/TNF ΔARE/+ brains, we evaluated protein levels of LC3 and the ratio between the LC3II and the LC3I forms of the protein which are indicative of increased autophagy.Western blot analysis in total brain protein extracts from 5XFAD/ TNF ΔARE/+ and 5XFAD control mice revealed a non-statistically significant increase in the levels of the LC3II form, providing evidence for a trend towards increase, in autophagy in the 5XFAD/TNF ΔARE/+ brains (Fig.…”

SSH1 impedes SQSTM1/p62 flux and MAPT/Tau clearance independent of CFL (cofilin) activation

“…Accumulation of toxic protein assemblies and dysfunctional mitochondria are associated with synaptic and neuronal loss in multiple neurodegenerative disorders. Such accumulations are thought to arise in large part from clearance deficits in the autophagy-lysosome system [1][2][3][4][5][6][7]. Selective autophagy is a major type of autophagy characterized by the recognition and degradation of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens [8][9][10][11][12][13][14].…”