Intrahippocampal Injection of a Lentiviral Vector Expressing Nrf2 Improves Spatial Learning in a Mouse Model of Alzheimer's Disease

The amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-β (Aβ) 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 transcrip...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences of the United States of America. - National Academy of Sciences. - 106(2009), 38, Seite 16505-16510
1. Verfasser:	Kanninen, Katja (VerfasserIn)
Weitere Verfasser:	Heikkinen, Riikka, Malm, Tarja, Rolova, Taisia, Kuhmonen, Susanna, Leinonen, Hanna, Ylä-Herttuala, Seppo, Tanila, Heikki, Levonen, Anna-Liisa, Koistinaho, Milla, Koistinaho, Jari, Hökfelt, Tomas
Format:	Online-Aufsatz
Sprache:	English
Veröffentlicht:	2009
Zugriff auf das übergeordnete Werk:	Proceedings of the National Academy of Sciences of the United States of America
Schlagworte:	amyloid-beta astrocyte heme oxygenase-1 microglia oxidative stress Biological sciences Physical sciences Health sciences


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100	1		\|a Kanninen, Katja \|e verfasserin \|4 aut
245	1	0	\|a Intrahippocampal Injection of a Lentiviral Vector Expressing Nrf2 Improves Spatial Learning in a Mouse Model of Alzheimer's Disease
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520			\|a The amyloid hypothesis of Alzheimer's disease (AD) postulates that amyloid-β (Aβ) 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 Aβ toward an insoluble Aβ pool without concomitant change in total brain Aβ 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.
650		4	\|a amyloid-beta
650		4	\|a astrocyte
650		4	\|a heme oxygenase-1
650		4	\|a microglia
650		4	\|a oxidative stress
650		4	\|a Biological sciences \|x Biology \|x Cytology \|x Cell biology \|x Cells \|x Neurons
650		4	\|a Biological sciences \|x Biology \|x Anatomy \|x Nervous system \|x Central nervous system \|x Brain \|x Hippocampus
650		4	\|a Physical sciences \|x Chemistry \|x Chemical compounds \|x Chemicals \|x Acids \|x Nucleic acids \|x RNA \|x Messenger RNA
650		4	\|a Biological sciences \|x Biology \|x Physiology \|x Physiological regulation \|x Homeostasis \|x Metabolic stress \|x Oxidative stress
650		4	\|a Health sciences \|x Medical conditions \|x Diseases \|x Nervous system diseases \|x Central nervous system diseases \|x Neurological disorders \|x Brain disorders \|x Alzheimers disease
650		4	\|a Biological sciences \|x Biology \|x Anatomy \|x Nervous system \|x Central nervous system \|x Brain
650		4	\|a Physical sciences \|x Chemistry \|x Chemical compounds \|x Chemicals \|x Polymers \|x Biopolymers \|x Proteins \|x Amyloids
650		4	\|a Physical sciences \|x Physics \|x Microphysics \|x Molecular physics \|x Molecules \|x Antioxidants
650		4	\|a Biological sciences \|x Biology \|x Zoology \|x Animals \|x Mammals \|x Primates \|x Humans
650		4	\|a Biological sciences \|x Biology \|x Cytology \|x Cell biology \|x Cells \|x Neuroglia \|x Astrocytes
650		4	\|a Biological sciences \|x Biology \|x Cytology \|x Cell biology \|x Cells \|x Neurons
650		4	\|a Biological sciences \|x Biology \|x Anatomy \|x Nervous system \|x Central nervous system \|x Brain \|x Hippocampus
650		4	\|a Physical sciences \|x Chemistry \|x Chemical compounds \|x Chemicals \|x Acids \|x Nucleic acids \|x RNA \|x Messenger RNA
650		4	\|a Biological sciences \|x Biology \|x Physiology \|x Physiological regulation \|x Homeostasis \|x Metabolic stress \|x Oxidative stress
650		4	\|a Health sciences \|x Medical conditions \|x Diseases \|x Nervous system diseases \|x Central nervous system diseases \|x Neurological disorders \|x Brain disorders \|x Alzheimers disease
650		4	\|a Biological sciences \|x Biology \|x Anatomy \|x Nervous system \|x Central nervous system \|x Brain
650		4	\|a Physical sciences \|x Chemistry \|x Chemical compounds \|x Chemicals \|x Polymers \|x Biopolymers \|x Proteins \|x Amyloids
650		4	\|a Physical sciences \|x Physics \|x Microphysics \|x Molecular physics \|x Molecules \|x Antioxidants
650		4	\|a Biological sciences \|x Biology \|x Zoology \|x Animals \|x Mammals \|x Primates \|x Humans
650		4	\|a Biological sciences \|x Biology \|x Cytology \|x Cell biology \|x Cells \|x Neuroglia \|x Astrocytes
655		4	\|a research-article
700	1		\|a Heikkinen, Riikka \|e verfasserin \|4 aut
700	1		\|a Malm, Tarja \|e verfasserin \|4 aut
700	1		\|a Rolova, Taisia \|e verfasserin \|4 aut
700	1		\|a Kuhmonen, Susanna \|e verfasserin \|4 aut
700	1		\|a Leinonen, Hanna \|e verfasserin \|4 aut
700	1		\|a Ylä-Herttuala, Seppo \|e verfasserin \|4 aut
700	1		\|a Tanila, Heikki \|e verfasserin \|4 aut
700	1		\|a Levonen, Anna-Liisa \|e verfasserin \|4 aut
700	1		\|a Koistinaho, Milla \|e verfasserin \|4 aut
700	1		\|a Koistinaho, Jari \|e verfasserin \|4 aut
700	1		\|a Hökfelt, Tomas \|e verfasserin \|4 aut
773	0	8	\|i Enthalten in \|t Proceedings of the National Academy of Sciences of the United States of America \|d National Academy of Sciences \|g 106(2009), 38, Seite 16505-16510 \|w (DE-627)254235379 \|w (DE-600)1461794-8 \|x 10916490 \|7 nnas
773	1	8	\|g volume:106 \|g year:2009 \|g number:38 \|g pages:16505-16510
856	4	0	\|u https://www.jstor.org/stable/40485096 \|3 Volltext
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952			\|d 106 \|j 2009 \|e 38 \|h 16505-16510