Despite its long and distinguished history in Alzheimer’s research, the microtubule-stabilizing protein tau still poses many a riddle to scientists. They do know that excessive phosphorylation of tau somehow figures in neurodegeneration, yet which kinase enzymes start this process, which ones egg it on, and where along the way the neuron sustains damage are among the questions that still confound them. A paper in today’s Neuron moves the story forward. It introduces a new animal model of tauopathy and proposes that the kinase CDK5, while not the sole instigator, is key to tangle formation and greatly worsens the progression of neurofibrillary pathology, at least in these mice.
Wendy Noble, working with Karen Duff at the Nathan S. Kline Institute of New York University in Orangeburg and colleagues there and elsewhere, crossed mice transgenic for increased CDK5 activity (Ahlijanian et al., 2000) with other transgenics overexpressing the mutant human P301L form of tau (Lewis et al., 2000) that are predisposed to tau pathology. The researchers did that because prior reports have implicated CDK5 activity driven by its cofactor p25 to be elevated in AD, and have shown that CDK5 can phosphorylate tau at sites relevant to AD (see, for example, ARF related news story). Tantalizingly, the CDK5 inhibitor roscovitine reduces tau pathology and neurodegeneration in a mouse model (see ARF related news story). And yet, CDK5 overexpression in mice is insufficient to produce tangles, indicating that other factors are at play (Bian et al., 2002; ARF related news story).
The combined model presented here shows a more pronounced phenotype, Noble and colleagues report. The mice do not have elevated CDK5 expression, but the enzyme’s activity is up roughly twofold. That enhancement came with a marked increase in tau hyperphosphorylation and tau aggregation in the brainstem and in the cortex. The double-transgenics also had more tangles in the brainstem-though no tangles in the cortex-than did the single-transgenic P301L mice, Noble et al. report. (The P301L single-transgenic have no tau pathology in the cortex, the authors point out.) Noble and colleagues also report data on GSK3, another leading suspect among tau-phosphorylating kinases and a drug target (see related news story). Like CDK5, GSK3 also showed increased activity in the double transgenics, and confocal microscopy suggests that both kinases co-localize with tau and even with each other in the cell body and some processes of cultured neurons, Duff’s team writes.
In spite of the intensified neurofibrillary pathology in the brainstem of the double-transgenics, these animals did not suffer an accelerated version of the dystonia seen in the P301T mice, at least by one year of age, the researchers note.
Putting their data in context, the authors propose a sequence of events whereby, once aberrant phosphorylation by CDK5 and/or other kinases has begun, tau proteins no longer bind microtubules, but instead become cytoplasmic and then redistributed away from the axon to the cell body, where they polymerize, fibrillize, and aggregate. During this entire time, tau phosphorylation by GSK3, CDK5, and other kinases may well continue even while tangles are already forming, the authors suggest.
Numerous animal models of tau exist by now, ranging from fly to mouse, from CDK5 to GSK3, from transgenes of mouse tau to human tau, from expression in motor and corticohippocampal neurons to sensory neurons. While this variation makes extrapolation to human tau pathogenesis difficult, the scientists consider compelling their evidence that increased CDK5 activity can promote tangle formation in mice that are predisposed to tauophathy.
How does all this tie in with AD and the amyloid hypothesis? Many researchers think that amyloid can drive tau pathology, perhaps via CDK5 activity. For example, some have proposed that Aβ induces tau hyperphosphorylation, and that the protease calpain-which leads to increased CDK5 activity-is elevated in AD brain (see ARF related news story; Town et al., 2002). P301T mice develop more severe neurofibrillary pathology when crossed with mice producing excess Aβ (see ARF related news story). None of these pathways are proven to occur in human neurodegenerative diseases involving tau, but the cumulative evidence is suggestive enough to explore the use of kinase inhibitors to counteract the progression of neurofibrillary pathology, Duff and colleagues write.—Gabrielle Strobel
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