Nrf2 mediates the expression of BAG3 and autophagy cargo adaptor proteins and tau clearance in an age-dependent manner

• Published in: Neurobiology of aging 2018-03, Vol.63, p.128-139
• Main Authors: Tang, Maoping, Ji, Changyi, Pallo, Susanne, Rahman, Irfan, Johnson, Gail V.W.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aging - genetics; Aging - metabolism; Aging - pathology; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy - genetics; Autophagy - physiology; Autophagy adaptors; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; BAG3; Brain - metabolism; Brain - pathology; Gene Expression - genetics; Mice, Inbred C57BL; Mice, Knockout; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; NF-E2-Related Factor 2 - metabolism; NF-E2-Related Factor 2 - physiology; Nrf2; Tau; tau Proteins - metabolism
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.12.001

During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2–associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (−/−) mice. We also analyzed the levels of total tau and phospho-tau species. There were minimal differences in the expression of autophagy-related genes or tau species in 4-month-old animals; however, by 12 months, all of these autophagy-associated genes were expressed at significantly lower levels in the Nrf2 (−/−) mice. The decreases in the autophagy-associated genes were accompanied by significantly elevated levels of phospho-tau species in the 12-month-old Nrf2 (−/−) brains. These findings indicate that Nrf2 regulation of autophagy-related genes likely plays a greater role in mediating the clearance of tau as an organism ages.