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

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

J Neurosci Res. 2017 Aug 12;:

Authors: Álvarez-Arellano L, Pedraza-Escalona M, Blanco-Ayala T, Camacho-Concha N, Cortés-Mendoza J, Pérez-Martínez L, Pedraza-Alva G

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.

PMID: 28801921 [PubMed – as supplied by publisher]

from #PM All via ola Kala on Inoreader http://ift.tt/2wGe0Vo

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