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The Journal of Neuroscience, April 4, 2007, 27(14):3712-3721; doi:10.1523/JNEUROSCI.0059-07.2007

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Neurobiology of Disease
Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting ß-Amyloid Burden

Tarja M. Malm,¹ Henna Iivonen,¹ Gundars Goldsteins,¹ Velta Keksa-Goldsteine,¹ Toni Ahtoniemi,¹ Katja Kanninen,¹ Antero Salminen,^2,4 Seppo Auriola,³ Thomas Van Groen,² Heikki Tanila,^1,4 and Jari Koistinaho^1,5

¹A. I. Virtanen Institute for Molecular Sciences and Departments of ²Neuroscience and Neurology and ³Pharmaceutical Chemistry, University of Kuopio, and Departments of ⁴Neurology and ⁵Oncology, Kuopio University Hospital, FIN-70211 Kuopio, Finland

Correspondence should be addressed to Dr. Jari Koistinaho, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Email: jari.koistinaho{at}uku.fi

Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-B (NF-B), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia–ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3ß (GSK-3ß). Because chronic inflammation, oxidative stress, and increased GSK-3ß activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering ß-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-B were not part of the brain pathology. Instead, the phosphorylated form of GSK-3ß was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3ß. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric Aß and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt–GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu²⁺ into a cell, and, in turn, Cu²⁺ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu²⁺-activated Akt pathway.

Key words: Alzheimer's disease; inflammation; glycogen synthase; phosphorylation; ß-amyloid; learning and memory

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Received Aug. 29, 2006; accepted Feb. 18, 2007.

Correspondence should be addressed to Dr. Jari Koistinaho, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Email: jari.koistinaho{at}uku.fi

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