Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease.

Based on a growing literature, cyclin-dependent kinase 5 (Cdk5) has been implicated in the pathological processes that contribute to neurodegeneration in Alzheimer's disease (AD). Cdk5 is ubiquitously expressed, but its activity is largely localized to post-mitotic neurons due to neuron-specific expression of its activators p35 and p39. Sufficient Cdk5 activity is critical to normal central nervous system development, as in its absence, neuronal migration and axonal path finding are deranged. Conversely, excessive and mislocalized Cdk5 activity appears to be detrimental to neuronal function. In fact, the pathological hallmarks of AD, beta-amyloid aggregates and neurofibrillary tangles, have been linked to Cdk5-mediated neuronal death. In this model, beta-amyloid is the toxic stimulus that disrupts intracellular calcium homeostasis, leading to activation of calpains, a family of calcium-dependent proteases. Calpain-mediated cleavage of p35, yields a truncated p25 fragment that possesses a longer half-life, lacks the necessary sequence targeting it to membranes, but retains the capacity to activate Cdk5. The resulting excessive and mislocalized Cdk5 activity targets tau as a substrate for hyperphosphorylation, which is a prerequisite of paired helical filament (PHF) formation. A number of recent reports, utilizing diverse methods, lend further support to this model of AD neurodegeneration, and several strategies for combating Cdk5 dysregulation have even been devised. However, the study of Cdk5 in AD is not without controversy, and questions remain regarding its role in the pathology. Herein, the most recent findings regarding this model are reviewed.

Cyclin-dependent kinase inhibitors: cancer killers to neuronal guardians.

The development of small molecule kinase inhibitors as potential cancer therapeutics is an area of intense interest, and a subset of these agents target cyclin-dependent kinase (CDK) activity. Ten distinct CDKs (1-9, 11), when paired with their cyclin activators, are integral to such diverse processes as cell cycle control, neuronal development, and transcriptional regulation. Mutation and/or aberrant expression of certain CDKs and their regulatory counterparts are associated with uncontrolled proliferation and tumorigenesis. As such, CDK selective inhibitors (CDKIs) that attenuate or prevent tumor growth have been developed. Recently, interest in the therapeutic potential of CDKIs has expanded to include neurodegenerative diseases, where dysregulated CDK activity has been linked to the pathogenesis of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and stroke. Specifically, aberrant activation of cell cycle CDKs or CDK5 is associated with apoptosis and neuronal dysfunction in response to various neuronal stressors. To date, CDKIs have shown promise as neuroprotective agents in the research laboratory and, in the future, may prove useful in the neurology clinic.

A spring-activated tilting apparatus for the study of balance control in man.

A tilting apparatus has been designed and constructed to produce fore-aft whole head-and-body tilt (WHBT) alone, or in combination with ankle dorsiflexion of standing subjects, about an axis colinear with the ankle joint. The apparatus is composed of a vertical tilting structure attached to a supporting base. Mechanical rotation of the vertical tilting structure is achieved by a spring activating system mounted on its base. Subjects are secured to the vertical structure by a body harness system with the head fixed, and the feet secured to the standing platform. Simultaneous dynamic WHBT and ankle joint displacement are induced by rotating the vertical support; whereas WHBT alone is achieved by concurrent rotation of both the vertical support and standing platform. Tilts are triggered manually, and data acquisition precedes head acceleration onset by 50-100 ms to provide suitable baseline values. This tilting apparatus has been successfully used to apply forward WHBT in 34 subjects with height ranging from 1.55 to 1.87 m and weights from 42 to 95 kg, and at magnitudes of peak head acceleration varying from 0.4 to 2.2 g as measured by a linear accelerometer mounted on a dental bite. These acceleration rates can be reproduced with minor variation in the same subjects. Moreover, the area under the head acceleration traces was reproducible within 15% between subjects. Tilts can be delivered with concomitant ankle dorsiflexion. These features make the low-cost tilting apparatus a very useful tool for the study of human tilting reactions in both laboratories and clinical settings.