| First Author | Joshi G | Year | 2015 |
| Journal | Neurobiol Aging | Volume | 36 |
| Issue | 2 | Pages | 664-79 |
| PubMed ID | 25316599 | Mgi Jnum | J:329737 |
| Mgi Id | MGI:6839172 | Doi | 10.1016/j.neurobiolaging.2014.09.004 |
| Citation | Joshi G, et al. (2015) Increased Alzheimer's disease-like pathology in the APP/ PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36(2):664-79 |
| abstractText | The presence of senile plaques is one of the major pathologic hallmarks of the brain with Alzheimer's disease (AD). The plaques predominantly contain insoluble amyloid beta-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named beta and gamma secretase, generate the neurotoxic amyloid-beta peptide from APP. Mature APP is also turned over endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders, and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Abeta processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Abeta (1-42), and Abeta (1-40), without a change total full-length APP. There was a shift of APP and Abeta into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2-deficient mice. Finally, neurons in the APP/PS1/Nrf2-/- mice had increased accumulation of multivesicular bodies, endosomes, and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD. |
