Sci. Aging Knowl. Environ., 8 February 2006
Vol. 2006, Issue 5, p. pe5
[DOI: 10.1126/sageke.2006.5.pe5]

PERSPECTIVES

When Good Cdk5 Turns Bad

Qing Guo

The author is in the Department of Physiology at The University of Oklahoma Health Sciences Center, College of Medicine, Oklahoma City, OK 73104. E-mail: qing-guo{at}ouhsc.edu

http://sageke.sciencemag.org/cgi/content/full/2006/5/pe5

Key Words: Alzheimer's disease • cyclin-dependent kinase 5 • p25 • amyloid beta peptide • tau

Introduction

Cyclin-dependent kinase-5 (Cdk5) is an essential factor in regulating neuronal migration and development (1). In addition, there is abundant evidence that Cdk5 regulates neuronal survival, synaptic plasticity, and learning and memory in the adult brain (2-8). At the same time, aberrant Cdk5 activity has been implicated in a variety of neurodegenerative conditions affecting the peripheral nervous system, such as peripheral nerve injury (9), and the central nervous system (CNS), such as Alzheimer's disease (AD) (10-14), Parkinson's disease (15, 16), amyotrophic lateral sclerosis (17-19), brain ischemia (20, 21), and convulsive seizures (22-24). Indeed, aberrant Cdk5 activity seems to be rapidly becoming the neuronal killer of choice in many experimental model systems of neurodegeneration and neuronal injury. What these studies are beginning to reveal is that Cdk5 appears to play critical and yet opposing roles, depending on how it is activated and possibly on the type of cells in which its function is evaluated. A recent study published in the 8 December 2005 issue of Neuron begins to provide an explanation for these contrasting roles of Cdk5 (25).

Cdk5 Actions on the Brain

Cdk5 is a 33-kDa proline-directed protein kinase that phosphorylates serine and threonine residues immediately preceding a proline residue (6, 11, 26-30). Proteins that have been shown to be phosphorylated by Cdk5 include (i) cytoskeletal elements; (ii) cell adhesion molecules; (iii) proteins involved in membrane cycling, axonal transport, and synaptic plasticity; and (iv) signal transduction kinases involved in cytoskeletal regulation or neuronal migration (1, 5, 8, 14, 26, 28, 30-34). The Cdk5 monomer has negligible enzymatic activity; it is activated by two neuron-specific proteins named p35 and p39, as well as by a proteolytic product of p35 called p25. Although Cdk5 is expressed in most tissues, its activity is largely restricted to neurons, because p35, p25, and p39 are mainly expressed in neurons (26, 28-30).

Like Cdk5, p35 is considered an integral player in the proper development of the mammalian CNS, and evidence suggests that p35 activates Cdk5 predominantly under normal physiological (rather than pathological) conditions. For example, it is known that hyperphosphorylation of the protein tau, which is a substrate of Cdk5, leads to neurofibrillary tangles in AD. However, triple transgenic mice that overexpress human p35, Cdk5, and tau do not exhibit an increase in the phosphorylation of tau, despite considerable increases in Cdk5 activity (35) (see "Detangling Alzheimer's Disease").

Homozygous deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning in mice (36). Analysis of these mice also revealed an essential role for Cdk5 in regulating the development of motor axons and neuromuscular synapses. Furthermore, p35 activation of Cdk5 appears to affect long-term depression (LPD) and long-term potentiation (LTP), the weakening and strengthening, respectively, of synapses, which represent the cellular basis for memory formation. Mice deficient in p35 exhibit a considerable decrease in Cdk5 activity, as well as impaired LPD and depotentiation of LTP in the Schaffer collateral CA1 pathway in the hippocampus, an axonal pathway that is integral to the process of memory formation. These findings suggest that p35-dependent Cdk5 activity is important to learning and synaptic plasticity (36, 37).

In contrast, p25 expression has been linked to neuronal dysfunction and cell death under pathological conditions (25, 38, 39). The p25 fragment is produced by the cleavage of p35 between residues 98 and 99 by calpain (a calcium-activated protease involved in neuronal cell death) (12, 25, 40, 41). This cleavage can be induced experimentally under neurodegenerative conditions; for example, the addition of amyloid beta peptide (A beta), derived from the amyloid beta precursor protein, to primary neurons has been shown to increase the conversion of p35 to p25 (12). Like p35, p25 activates Cdk5, but because it is more stable than p35, the fragment can cause prolonged activation of Cdk5. In addition, because p25 displays different subcellular localization from p35, its production may result in a redistribution of Cdk5 activity and, thus, altered substrate specificities (38, 42). Indeed, recombinant Cdk5 phosphorylates tau with higher efficiency when incubated in the presence of p25 than p35 in an in vitro assay (43).

Too Much of a Good Thing?

How can these opposing roles of Cdk5 in neuronal cell survival and death be reconciled? One possible explanation has to do with the manner in which Cdk5 is activated. Prolonged, aberrant overexpression of any protein may, in theory, turn a "good" protein "bad," resulting in conditions that prevent neurons from operating normally. In the case of Cdk5, a study by Andre Fischer and colleagues in Li-Huei Tsai's group at Harvard Medical School provides support for this hypothesis (25).

Fischer used transgenic mice (CK-p25 mice) carrying a human p25 gene under the control of the CamKII inducible promoter, whose activity is induced by withdrawing doxycycline from the animals' food to demonstrate that p25 expression has opposing phenotypic consequences on synaptic plasticity, learning, and memory, depending on whether it is transiently or chronically expressed (25). In a previous report from the same group, CK-p25 mice were used to demonstrate that increased amounts of p25 and of Cdk5 activity were associated with hyperphosphorylation and accumulation of aggregated tau in vivo, which, in turn, coincided with the onset of substantial neuronal loss in the cerebral cortex and hippocampus (38). The phosphorylation of known physiological Cdk5 substrates, such as the proteins Nudel, mDab1, and PSD95, was not increased in transgenic mice, which suggests that, in addition to overactivating and redistributing Cdk5 activity, p25 might redirect Cdk5 activity to target substrates involved in neurodegeneration (38).

The current study was designed to study the functional consequences of p25 expression in CK-p25 mice. Elevated hippocampal Cdk5 activity was observed 1 to 2 weeks after inducing p25 expression, and neuronal loss was apparent in the hippocampus and cortex about 4 weeks after induction (25). Motor behavior and pain sensation were not altered in these animals, as determined by motor coordination in rotarod tests and in electric foot-shock tests. Extensive neurodegeneration was observed in mice after 6 weeks of continued p25 expression, but not after 2 weeks. As a result, subsequent behavioral tests were performed after inducing p25 expression for 2 and 6 weeks.

A common behavior test in mice involves eliciting fear responses through conditioned stimuli that were previously neutral, such as a particular chamber (context) or auditory cue (tone), but that have been paired with a painful unconditioned stimulus, such as foot shock. In such tests, freezing is a common response of the mice, which is used as an index of fear conditioning. Fischer and colleagues reported that six weeks of p25 expression resulted in a biphasic change (an increase followed by decrease) in the ability to form new memories, as measured by context- and tone-dependent freezing behavior tests. Because the hippocampus is involved in context-dependent fear conditioning, whereas the amygdala is involved in tone-dependent fear conditioning (44), these results indicate that prolonged expression of p25 (for 6 weeks) impairs both hippocampus-dependent associative memory and amygdala-dependent memory, two distinct types of learning and memory processes. In contrast, transient (2 weeks) induction of p25 expression selectively enhanced hippocampus-dependent associative memory without affecting amygdala-dependent memory.

These observations were further substantiated with data from Morris water-maze tests, commonly used tests that study learning by evaluating an animal's ability to find a hidden platform in a pool of water over a number of trials. The investigators showed that spatial learning and memory were initially enhanced by transient p25 expression but impaired by chronic increases in p25 amounts. The authors went on to show that transient p25 expression enhances the animals' ability to acquire new memories for up to 4 weeks without inducing neurodegeneration, whereas continuous p25 expression (for 6 weeks) results in astrogliosis, neuronal loss, and cognitive decline.

Electrophysiological data obtained from hippocampal slices supports the results of the behavioral analyses. Field excitatory postsynaptic potentials were evoked at the CA1 synapses by stimulating Schaffer collaterals at a low frequency (one stimulation per minute) to establish a stable baseline of field potentials, followed by a high-frequency sequence of stimulations to induce LTP. As expected, transient expression of p25 enhanced LTP, whereas prolonged expression decreased it. In addition, morphological data showed that transient expression of p25 increased the dendritic spine density of the CA1 pyramidal neurons, as measured by Golgi impregnation (a method that uses the staining of brain sections with Golgi-Cox solution) and by the number of the synapses in the CA1 stratum radiatum, as measured by the presence of the electron-dense postsynaptic density juxta-opposed to the presynaptic terminal containing synaptic vesicles (visualized by transmission electron microscopy) and of presynaptic protein synaptophysin (visualized by immunohistochemistry). An increase in the number of synapses could be a contributing factor for the enhanced LTP as measured in this study. In contrast, significantly fewer synapses were observed in mice with prolonged expression of p25.

However, like the CK-p25 mice induced for 2 weeks, those induced for 6 weeks still exhibited a higher number of spines per dendrite than control animals. It is not clear how this observation ties in with the impaired behavioral performance of these animals. However, it is possible that these mice lost many neurons, despite having a higher number of spines per dendrite in the neurons that remain. Further evidence that Cdk5 activity is necessary for dendritic spine formation came from experiments showing that spine density of the CA1 pyramidal neurons was significantly reduced in both p35 null and heterozygous p35-deficient mice, which have much lower amounts of Cdk5 activity.

Thus, these behavioral, electrophysiological, and morphological data indicate that transient p25 expression facilitates learning and synaptic growth, whereas prolonged p25 expression impairs learning and synaptic plasticity (with the exception of spines per dendrite). The authors proposed that p25 production in vivo might not be detrimental to learning or synaptic plasticity on its own but can lead to neuronal cell death when p25 levels are chronically high. They further suggested that p25-mediated facilitation of behavioral performance (LTP and synaptogenesis) may represent a compensatory mechanism of neurons in response to neurodegenerative risk factors in diseases such as AD. In this scenario, chronic exposure to AD risk factors would continue to increase p25 levels to a critical concentration that ultimately contributes to neuronal loss. Therefore, increased p25 levels are likely to be an early event in AD pathogenesis, at first providing some benefit and later contributing to disease pathogenesis.

Unanswered Questions

The precise cellular and molecular mechanisms by which p25 promotes neuronal survival and differentiation, and learning and memory, and by which "good" Cdk5 activity is turned to "bad" by p25 remain unclear. For example, convincing evidence linking aberrant Cdk5 activity to known apoptotic machinery is lacking. It is also unclear what role aberrant Cdk5 activity plays in neurodegenerative diseases. Published analyses of changes in the concentration of p25 in AD brain tissues have reported conflicting results (3, 45-47). In one carefully controlled study, the highest p25 amounts were observed in the majority of age-matched control samples, rather than in samples from patients with AD or other tauopathies (46). There was also no correlation between hyperphosphorylated tau and elevated p25 or Cdk5 amounts in AD brains. In addition, some studies indicate that tau may not be directly phosphorylated by Cdk5, although the effects of Cdk5 on the status of tau phosphorylation may be context dependent (18, 35, 48-50). In p35 null mice, which have much lower Cdk5 activity, tau phosphorylation is actually increased (51). In addition, mice overexpressing p25 do not display enhanced tau phosphorylation or cell death (45). Thus, understanding the role that Cdk5 plays in neurodegeneration and the mechanisms by which it acts awaits further study.

Conclusions

The study by Fischer and colleagues suggests that increased, prolonged activation of Cdk5 plays a role in neurodegeneration, but given the complex nature of Cdk5 functions, translating this finding into therapeutic approaches will be challenging at best. The substrates of Cdk5 are diverse, indicating that Cdk5 may play vital roles in a variety of physiological processes, in addition to the essential roles of p25-activated Cdk5 in synaptic plasticity reported in the paper by Tsai's group (25). The observations that Cdk5 is involved in neuronal protection (52), axonal regeneration (53), and neuronal cell destruction (26, 38) indicate that Cdk5 regulates both life and death processes. In addition, it is possible that p35 and p25 have a differential effect on the substrate specificity of Cdk5 (54) and that Cdk5 may have different effects depending on cell types and organisms. Indeed, before the publication of Fischer and colleagues, it had been reported that mice expressing low levels of p25 in the postnatal forebrain show increased performance in learning and memory tasks (55) and that the effect of low-level p25 expression on hippocampal synaptic plasticity and spatial learning is sex-specific (e.g., it is observed in female but not in male mice) (56). The neuroprotective actions of Cdk5 and its inhibition of specific apoptotic pathways indicate that broadly blocking Cdk5 activity might increase neuronal cell death under certain conditions (57, 58). Thus, researchers should exercise caution before trying to use the inhibition of Cdk5 activity (by reducing the conversion of p35 to p25 or directly inhibiting Cdk5 activity) as a potential therapeutic option for treating AD and other neurodegenerative disorders.


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Citation: Q. Guo, When Good Cdk5 Turns Bad. Sci. Aging Knowl. Environ. 2006 (5), pe5 (2006).




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