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Role of the transcription factor NRF2 in the regulation of macroautopahgy and its impact in a new mouse model of AD

AuthorsPajares, Marta; Jiménez-Moreno, Natalia; García-Yagüe, Ángel Juan; Escoll, Maribel; Rojo, Ana I. CSIC ORCID; Cuadrado, Antonio CSIC ORCID
Issue Date2016
Citation3rd Symposium on Biomedical Research (2016)
AbstractAutophagy is a precise and coordinated process essential for non-dividing cells, such as neurons. Indeed, its failure has been related to the development of many neurodegenerative diseases, such as Alzheimer’s Disease (AD). While the regulation of autophagy at the level of cell signalling and protein interactions is being elucidated, less is known about transcriptional regulation of autophagy. A bioinformatics analysis allowed us to identify several putative ARE-containing autophagy genes. Some of these were validated as NRF2 regulated AREs by additional chromatin immunoprecipitation assays and quantitative RT-PCR of human and mouse cells after NRF2 activation with sulforaphane. Mouse embryo fibroblasts of Nrf2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NRF2 expressing lentivirus. To explore the impact of NRF2 deficiency in protein clearance in vivo, we generated a new AD mouse model consisting on expression of human APPV717I and TAUP301L in the wild type (AT-Nrf2-WT) and in the Nrf2-knockout genetic background (AT-Nrf2-KO). All mice developed amyloid plaques after 13-14 months, but AT-Nrf2-KO mice exhibited a larger number of intracellular APP-positive granules. Moreover, intracellular insoluble TAU aggregates were more evident in hippocampus of AT-Nrf2-KO mice. Indeed, APP and TAU co-localized with the autophagy marker p62, but ATNrf2-KO mice showed lower colocalization, suggesting alterations in the autophagy flux. In AD patients, neurons expressing high levels of APP or TAU also expressed SQSTM1/p62 and nuclear NRF2, suggesting their attempt to degrade intraneuronal aggregates through this autophagy pathway. This study shows that NRF2 modulates autophagy gene expression and offers a new therapeutic strategy to combat proteinopathies.
DescriptionResumen del póster presentado al 3rd Symposium on Biomedical Research: "Advances and Perspectives in Neuroscience", celebrado en la Universidad Autónoma de Madrid el 22 de abril de 2016.
Appears in Collections:(IIBM) Comunicaciones congresos
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