In the September 21 online Nature Neuroscience, YouMing Lu and colleagues at the University of Calgary, Canada, report that the serine-threonine kinase Cdk5, which is known to phosphorylate the neurofibrillary tangle protein tau, is essential for ischemia-provoked death of hippocampal CA1 neurons. Lu was prompted to investigate the role of the cyclin-dependent kinase because of a previous report that p25, a truncated, persistent form of the Cdk5 activator p35, is found in rat forebrain following cerebral ischemia (see ARF related news story). Significantly, p25 has also been shown to accumulate in the brains of Alzheimer's patients, leading to tau phosphorylation(see ARF related news story).
To test the relationships among p25, Cdk5, and cell death, first author Jian Wang and colleagues quantified the amounts of the two proteins in CA1, CA3, and dentate gyrus extracts taken from either control mice or those that had suffered from transient forebrain ischemia. Only the CA1 neurons from ischemic animals showed accumulation of p25. In addition, levels of activated Cdk5 increased in these neurons fourfold as compared to samples from sham-treated animals. Next, to probe the role played by Ckd5 in neuronal death, the authors infected the animals with a virus carrying a dominant-negative form of the kinase. When these animals were subjected to ischemia, the CA1 neurons were protected as judged by Fluoro-Jade and NeuN staining, which reveal degenerating and surviving neurons, respectively. Without the dominant-negative protein, the numbers of dying neurons skyrocketed from about 250 per square millimeter to almost 2,500.
How might Cdk5 contribute to the death of neurons? It is known that in vitro, the kinase can phosphorylate the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor. To test if this is also true in vivo, the authors raised an antibody that recognizes specifically Cdk5 phosphorylated NR2A (on serine 1232). This antibody allowed them to detect a ~3.5-fold increase in ser1232 phosphorylated receptor in CA1 neurons following ischemia.
The data indicate that ischemia sets off a chain of events that includes the accumulation of p25, activation of Cdk5, and phosphorylation of the NMDA channel, which in turn leads to enhanced channel activity, a known contributor to neuronal death.
The events following stroke show striking parallels with those that occur in AD, where p25 causes phosphorylation of tau by Cdk5. Pressing questions now include: Why does p25 accumulate, and what explains the exquisite neuronal specificity of these cascades?—Tom Fagan
- Wang J, Liu S, Fu Y, Wang JH, Lu Y. Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci. 2003 Oct;6(10):1039-47. PubMed.