Cell cycle proteins in Alzheimer's disease: Plenty of wheels but no cycle

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The unexpected presence of certain control elements of the cell cycle in susceptible neurons in AD not only provides a possible explanation for many of the pathological aspects of the disease, but also suggests a crucial role for temporally ectopic cell cycle dysregulation driving proximal pathophysiology and cell death in AD. This process may be precipitated by alterations in and/or sensitivity of signal transduction pathways that are stimulated by growth factors such as NGF, TGF and bFGF, or inflammatory cytokines, all of which are increased in AD brain. While it has been argued that expression and activation of cell cycle proteins leads to cell cycle progression, DNA replication and cell death via a mitotic catastrophe, we favor a model in which cell cycle proteins that traditionally function at different stages of the cell cycle directly and concurrently participate in regulating gene expression and sprouting, formation of pathologic lesions associated with AD, and cell death mechanisms (Fig. 2). Importantly, these cell cycle protein responses may be susceptible to pharmacological interventions that disrupt cell cycle activation, thereby providing new and exciting potential therapeutic interventions for AD. Future studies should explore the possible utility of cyclin/CDK inhibitors or other agents that directly modify the function of cell cycle proteins in reducing neuronal cell death and impeding NFT formation during AD. In addition, the signal transduction pathways that regulate cell cycle protein activation or re-distribution are also potential targets for therapeutic intervention. Finally, altered function or distribution of cell cycle transcriptional regulators may alter chromatin structure and make the DNA more susceptible to oxidative induced damage, further adding to the degenerative state of the neuron. In conclusion, expression and activation of cell cycle proteins during AD likely occurs as a response to the initiating disease factors and directly participates in neuronal responses and cell death pathways during the disease process. While neurons may exit the GO phase of the cell cycle, progression through stages of the cycle or DNA replication are not necessary for cell cycle proteins to stimulate neuronal death during AD nor function in the phosphorylation of τ and development of NFTs.

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Journal of Alzheimer's Disease







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