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Signaling Mechanisms Underlying Aβ Toxicity: Potential Therapeutic Targets for Alzheimer's Disease

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The accumulation of amyloid β peptide (Aβ) is believed to be an early and critical event leading to synapse and neuronal cell loss in Alzheimer's Disease (AD). Aβ itself is toxic to neurons in vitro and the load of Aβ in vivo causes the loss of synapses and neurons in brain in animal models. Therefore, there has been considerable interest in elucidating the mechanism(s) of Aβ neurotoxicity. Here, we review the molecular signaling pathways involved in Aβ-induced cell death, including signaling through the neuronal nicotinic receptor and the Aβ-triggered generation of reactive oxygen species (ROS) leading to the activation of the c-jun N-terminal kinase (JNK), and the ensuing phosphorylation of p66Shc and inactivation of the Forkhead transcription factors. This focused review not only provides a better understanding of the signaling mechanisms involved in Aβ-induced cell death, but also underscores the potential of JNK, p66Shc, Forkhead proteins, p25/cdk5, and neuronal nicotinic receptor, as therapeutic targets for AD.

Keywords: Forkhead proteins; JNK; apoptosis; cdk5; neuronal nicotinic receptor; p66Shc; phosphorylation; reactive oxygen species

Document Type: Research Article


Affiliations: Division of Neurobiology,Department of Psychiatry, Johns Hopkins University School of Medicine,CMSC 9-125, 600 North Wolfe Street, Baltimore, MD 21287, USA.

Publication date: 2006-06-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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