Research article summary (published 8 Sep 2009):

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

Full Abstract

The amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-beta (Abeta) 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 Abeta toward an insoluble Abeta pool without concomitant change in total brain Abeta 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.

Author information

Author/s: Kanninen, Katja (K); Heikkinen, Riikka (R); Malm, Tarja (T); Rolova, Taisia (T); Kuhmonen, Susanna (S); Leinonen, Hanna (H); Ylä-Herttuala, Seppo (S); Tanila, Heikki (H); Levonen, Anna-Liisa (AL); Koistinaho, Milla (M); Koistinaho, Jari (J);

Affiliation: Departments of Neurobiology and Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, FI-70211 Kuopio, Finland.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A), published in United States. (Language: eng)

Reference: 2009-Sep; vol 106 (issue 38) : pp 16505-10

Dates: Created 2009/10/06; Completed 2009/11/06;

PMID: 19805328, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Alzheimer Disease - genetics; metabolism; therapy Amyloid beta-Protein Precursor - genetics; metabolism Animals Blotting, Western Disease Models, Animal Female Gene Therapy - methods Genetic Vectors - administration & dosage; genetics Green Fluorescent Proteins - genetics; metabolism Hippocampus - cytology; metabolism Humans Lentivirus - genetics Male

Male Maze Learning - physiology Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Confocal NF-E2-Related Factor 2 - genetics; metabolism; physiology Neurons - metabolism Presenilin-1 - genetics; metabolism Recombinant Fusion Proteins - genetics; metabolism Response Elements - genetics Reverse Transcriptase Polymerase Chain Reaction Space Perception - physiology

Associated Chemicals: Amyloid beta-Protein Precursor (0) ; NF-E2-Related Factor 2 (0) ; Presenilin-1 (0) ; Recombinant Fusion Proteins (0) ; Green Fluorescent Proteins (147336-22-9)

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