Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease

Abstract

The amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-␤ (A␤) deposition and neurotoxicity play a causative role in AD; oxidative injury is thought to be central in the pathogenesis. An endogenous defense system against oxidative stress is induced by binding of the transcription factor nuclear factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE) enhancer sequence. The Nrf2-ARE pathway is activated in response to reactive oxygen species to trigger the simultaneous expression of numerous protective enzymes and scavengers. To exploit the Nrf2-ARE pathway therapeutically, we delivered Nrf2 bilaterally into the hippocampus of 9-month-old transgenic AD mice (APP/PS1 mice) using a lentiviral vector encoding human Nrf2. The data indicate that significant reductions in spatial learning deficits of aged APP/PS1 mice in a Morris Water Maze can be achieved by modulating levels of Nrf2 in the brain. Memory improvement in APP/PS1 mice after Nrf2 transduction shifts the balance between soluble and insoluble A␤ toward an insoluble A␤ pool without concomitant change in total brain A␤ burden. Nrf2 gene transfer is associated with a robust reduction in astrocytic but not microglial activation and induction of Nrf2 target gene heme oxygenase 1, indicating overall activation of the Nrf2-ARE pathway in hippocampal neurons 6 months after injection. Results warrant further exploration of the Nrf2-ARE pathway for treatment of AD and suggest that the Nrf2-ARE pathway may represent a potential therapeutic strategy to pursue in AD in humans, particularly in view of the multiple mechanisms by which Nrf2 can exert its protective effects.amyloid-beta ͉ astrocyte ͉ heme oxygenase-1 ͉ microglia ͉ oxidative stress

Lentiviral Delivery of a Vesicular Glutamate Transporter 1 (VGLUT1)-Targeting Short Hairpin RNA Vector Into the Mouse Hippocampus Impairs Cognition

“…Two independent groups also failed to observe any impairment of VGLUT1 heterozygous mice during acquisition or probe trials in a Morris water maze reference memory task similar (but not identical) to that used in the present study (Tordera et al, 2007;Balschun et al, 2010). The apparent spread of lentiviral particles following intrahippocampal injection is reported to be o0.5 mm using similar injection apparatus, rate, and volume of administration to the current study (Kanninen et al, 2009), and hence only B17% of the dorsal hippocampal tissue used for quantification of VGLUT1 mRNA and protein levels is likely to have been exposed to the VGLUT1-targeting shRNA vector. Immunohistochemical analysis of VGLUT1 expression in coronal brain slices showed a localized selective reduction extending B100 mm from the injection tract in VGLUT1-targeting shRNA-treated mice (but not controls) and being most evident in the stratum lacunosum-moleculare of CA1 and the polymorphic layer of the dentate gyrus.…”

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…Thus, SKN-1 appears functionally analogous to Nrf2, the best-studied member of the Nrf family, which controls phase II detoxification response genes and is centrally involved in cellular responses to oxidative stress (reviewed in Osburn and Kensler 2008). Nrf2 activation, either by tert-butylhydroquinone treatment or viral Nrf2 gene transfection, has been shown to be protective in an APP/PS1 transgenic mouse model (Kanninen et al 2008(Kanninen et al , 2009, as well as in neuronal cells exposed to exogenous Ab (Wruck et al 2008). Interestingly, a polymorphism in the human Nrf2 gene, NFE2L2, has recently been associated with earlier AD onset (Von Otter et al 2010).…”

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Nuclear response factor 2 (Nrf2) and Nrf2/antioxidant response element have been proposed as a therapeutic target for autophagy and mitophagy. In transgenic AD mouse models intrahippocampal injections of the lentiviral vector expressing Nrf2 decreased Aβ plaque, reduced learning deficits, and protected against Aβ-induced cell death [158,159]. Synthetic triterpenoids have been demonstrated to induce expression of Nrf2 and to protect against cell death in both in vitro and in vivo experiments [160,161].…”