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P4‐259: Mechanism for the protective effect of pyrrolidine dithiocarbamate against oxidative stress in AD: induction of the Nrf2‐ARE pathway
Author(s) -
Kanninen Katja,
Tarja Malm,
Giniatullina Raisa,
Crouch Peter,
Yamamoto Masayuki,
Giniatullin Rashid,
Goldsteins Gundars,
Levonen AnnaLiisa,
White Anthony,
Koistinaho Jari
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2296
Subject(s) - pyrrolidine dithiocarbamate , oxidative stress , reactive oxygen species , gsk 3 , pharmacology , chemistry , amyloid beta , gsk3b , neurotoxicity , microbiology and biotechnology , glycogen synthase , signal transduction , nf κb , toxicity , biochemistry , biology , phosphorylation , peptide , organic chemistry
Background:Oxidative injury is central in the pathogenesis of Alzheimer’s disease (AD). An endogenous defence system against oxidative stress is induced by binding of nuclear factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE). The Nrf2-ARE pathway is activated in response to reactive oxygen species to trigger the simultaneous expression of numerous protective proteins. We have previously demonstrated the potential of the Nrf2-ARE pathway as a therapeutic target in AD; in transgenic (APP/PS1) mice the Nrf2-ARE pathway is attenuated at the time of amyloid beta deposition, Nrf2 over-expression protects against amyloid beta toxicity, and Nrf2 gene delivery attenuates cognitive decline in APP/PS1 mice. Pyrrolidine dithiocarbamate (PDTC) scavenges reactive oxygen species and transports copper inside cells. We have previously shown that PDTC ameliorates cognitive dysfunction in APP/PS1 mice via inhibition of active glycogen synthase kinase-3b (GSK-3b). The fact that GSK-3b regulates nuclear translocation of Nrf2 suggests that the protective effect may be mediated by the Nrf2-pathway. This study aims to exploit the Nrf2-ARE pathway therapeutically by assessing the potential of PDTC to induce Nrf2 in in vitro and in vivomodels of AD.Methods: Neuronal cultures from wildtype and Nrf2 knock-out (KO)micewere used to assess the ability of PDTC to protect neurons against amyloid beta toxicity. Western blotting was used to study Nrf2pathway induction by PDTC in vitro. To assess the effect of PDTC in vivo, APP/PS1 mice were treated with PDTC in the drinking water for 10 months. Western blotting, qRT-PCR and measurement of oxidative stress were carried out to assess the protective effect and induction of the Nrf2-pathway. The copper content of the brain was measured with ICP-MS. Results: The finding that PDTC protects against amyloid beta toxicity in wildtype, but not in Nrf2-KO neurons suggests that the Nrf2-pathway is implicated in it’s protective action. PDTC also induces the expression of Nrf2-controlled proteins. Treating mice with PDTC increases the copper content of the brain and reduces oxidative stress. Conclusions: Considering that the Nrf2-pathway is impaired in AD, induction of this endogenous defence mechanism by molecules such as PDTC can be harnessed to combat neurodegeneration.