The Cell Cycle Cdc25A Tyrosine Phosphatase Is Activated in Degenerating Postmitotic Neurons in Alzheimer's Disease

Abstract

The Cdc25 phosphatases play key roles in cell-cycle progression by activating cyclin-dependent kinases. The latter are absent from neurons that are terminally differentiated in adult brain. However, accumulation of mitotic phosphoepitopes, and re-expression and activation of the M phase regulator, Cdc2/cyclin B, have been described in neurons undergoing degeneration in Alzheimer's disease (AD). To explain this atypical mitotic activation in neurons we investigated the Cdc2-activating Cdc25A phosphatase in human brain. The structural hallmarks of AD neurodegeneration, neurofibrillary tangles and neuritic plaques, were prominently immunolabeled with Cdc25A antibodies. In addition numerous neurons without visible structural alterations were also intensely stained, whereas control brain was very weakly positive. After immunoprecipitation from control and AD tissue, we found that the tyrosine dephosphorylating activity of Cdc25A against exogenous Cdc2 substrate was elevated in AD. Accordingly, Cdc25A from AD tissue displayed increased immunoreactivity with the mitotic phosphoepitope-specific antibody, MPM-2, and co-localized with MPM-2 immunoreactivity in AD neurons. These data suggest that Cdc25A participates in mitotic activation during neurodegeneration. The involvement of Cdc25A in cellular transformation, modulation of the DNA damage checkpoint, and linkage of mitogenic signaling to cell cycle machinery, also implicates one of these cell-cycle pathways in AD pathogenesis.

Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

“…This hypothesis is supported by observations on the expression of developmentally regulated genes in AD that correspond to a condition of dedifferentiation and links neurodegeneration to cell-cycle-related events (Heintz, 1993;Arendt et al, 2000). The re-expression of a multitude of cell-cycle regulators known to control the activation and progression of the cell cycle in dividing cells has been observed previously in degenerating neurons in AD (Smith and Lippa, 1995;Arendt et al, 1996Arendt et al, , 1998McShea et al, 1997;Nagy et al,1997a,b;Vincent et al, 1997;Busser et al, 1998;Ding et al, 2000). Moreover, applying fluorescence in situ hybridization (FISH) technique to paraffin sections of the adult human CNS, Yang et al (2001) could provide direct evidence for aneuploidy in AD, but not in normal brain.…”

Deregulated Cdk5 Triggers Aberrant Activation of Cell Cycle Kinases and Phosphatases Inducing Neuronal Death

“…Accumulating evidence has highlighted the reactivation of cell cycle in AD neurons as a potential mechanism that drives cells towards neuronal atrophy. The presence of ectopic markers like phosphorylated histone H3, replicated DNA, active Cdc25 isoforms and active Cdk1 support alterations in cell cycle control in AD etiology (Ding et al, 2000;Vincent et al, 2001;Vincent et al, 1997;Ogawa et al, 2003). Active Cdk1 and cyclin B1 colocalize with AD-specific mitotic phospho-epitopes, suggesting that Cdk1 may phosphorylate neuronal tau protein causing neurofibrillary tangles (NFT) formation (Vincent et al, 1997).…”

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

“…DSPases have also been implicated in AD (64). Cdc25A and Cdc25B are activated in the degenerating postmitotic neurons of AD patients (65,66). PTEN, a major negative regulator of the PI3k/Akt pathway, was found to be significantly less expressed in AD neurons, as well as being altered in distribution (49,67).…”