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 3␤ (GSK-3␤). Because chronic inflammation, oxidative stress, and increased GSK-3␤ 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 ␤-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-3␤ was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3␤. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric A␤ 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 Cu 2ϩ into a cell, and, in turn, Cu 2ϩ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu 2ϩ -activated Akt pathway.