title: Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy.
abstract: 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 β-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named β and γ secretase, generate the neurotoxic amyloid-β 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/Aβ 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, Aβ (1-42), and Aβ (1-40), without a change total full-length APP. There was a shift of APP and Aβ 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.
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, WI, USA.
authors.forename: Gururaj
authors.initials: G
authors.lastname: Joshi
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, WI, USA.
authors.forename: Kok Ann
authors.initials: KA
authors.lastname: Gan
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, WI, USA; Center of Neuroscience, University of Wisconsin-Madison, WI, USA; Waisman Center, University of Wisconsin-Madison, WI, USA.
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.affiliation: School of Pharmacy, University of Wisconsin-Madison, WI, USA; Molecular and Environmental Toxicology Center, University of Wisconsin-Madison, WI, USA; Center of Neuroscience, University of Wisconsin-Madison, WI, USA; Waisman Center, University of Wisconsin-Madison, WI, USA. Electronic address: jajohnson@pharmacy.wisc.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004195:Disease Models, Animal; D011992:Endosomes / Q000378:metabolism; D017353:Gene Deletion; D008247:Lysosomes / Q000378:metabolism; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse
keywords: Amyloid precursor protein (APP); Amyloid β peptide; Autophagy; mTOR pathway; p62/SQSTM