Abstract
The accumulation of amyloid β peptide (Aβ) is believed to be an early and critical event leading to synapse and neuronal cell loss in Alzheimers 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: JNK, p66Shc, Forkhead proteins, cdk5, apoptosis, phosphorylation, reactive oxygen species, neuronal nicotinic receptor
CNS & Neurological Disorders - Drug Targets
Title: Signaling Mechanisms Underlying Aβ Toxicity: Potential Therapeutic Targets for Alzheimers Disease
Volume: 5 Issue: 3
Author(s): Wanli W. Smith, Myriam Gorospe and John W. Kusiak
Affiliation:
Keywords: JNK, p66Shc, Forkhead proteins, cdk5, apoptosis, phosphorylation, reactive oxygen species, neuronal nicotinic receptor
Abstract: The accumulation of amyloid β peptide (Aβ) is believed to be an early and critical event leading to synapse and neuronal cell loss in Alzheimers 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.
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Cite this article as:
Smith W. Wanli, Gorospe Myriam and Kusiak W. John, Signaling Mechanisms Underlying Aβ Toxicity: Potential Therapeutic Targets for Alzheimers Disease, CNS & Neurological Disorders - Drug Targets 2006; 5 (3) . https://dx.doi.org/10.2174/187152706784111515
DOI https://dx.doi.org/10.2174/187152706784111515 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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