Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to ß-Amyloid peptide accumulation.
J Neurosci Res
; 96(2): 234-246, 2018 02.
Article
en En
| MEDLINE
| ID: mdl-28801921
ABSTRACT
ß-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 ß-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, ß-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 ß-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing ß-Amyloid peptides (5XFAD) but lacking caspase-1, presented reduced ß-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 ß-Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Autofagia
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Regulación de la Expresión Génica
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Caspasa 1
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Enfermedad de Alzheimer
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Inflamación
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Trastornos de la Memoria
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Neuronas
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Año:
2018
Tipo del documento:
Article