Title: Insights into neurodegeneration fromp25/cdk5
Description: Cyclin dependent kinase 5 (cdk5) is critically involved in multiple physiological processes in the central nervous system, both during development and in the adult brain. In neurotoxic conditions, the regulatory subunit of cdk5, p35, is cleaved to p25 by calpain, which results in hyperactivation of cdk5. The generation of p25 has been implicated in a number of neurodegenerative conditions including Alzheimer's disease and stroke. Postnatal, forebrain-specific overexpression p25 in an inducible transgenic mouse line (CK-p25) elicits neurodegeneration in the form of severe neuronal loss, tau abnormalities and neurofibrillary tangles, and cognitive decline, which recapitulates some of the major features of Alzheimer's disease. Here, I explore the mechanisms that are causally involved in p25 neurotoxicity. Neuronal cell cycle activity and generation of double strand breaks preceded neurodegeneration in CK-p25 mice, and at later stages were tightly associated with dying neurons. Inactivation of histone deacetylase 1 activity by p25/cdk5 was identified as an underlying mechanism for these events. Restoring HDAC1 activity resulted in protection against p25-mediated neurotoxicity in a cell culture model and protection in an in vivo model for ischemic stroke. These findings provide evidence that deregulation of chromatin leading to DNA damage and aberrant transcription is involved in the neurodegeneration observed in Alzheimer's disease and stroke.

The processing of amyloid precursor protein (APP) to generate beta amyloid (Aβ) is considered to be a central event in Alzheimer's disease pathogenesis. Surprisingly, p25 was found to modulate the production and intracellular accumulation of in AB in the CK-p25 mice. Disruption of axonal transport and upregulation of β-secretase cleavage of APP are suggested to be involved in this process. The NAD+ dependent deacetylase SIRT1 has been implicated in lifespan extension in a number of organisms. SIRT1 and resveratrol, a SIRT1 activating compound found in red wine, exhibited neuroprotective effects in the p25 neurotoxicity model as well as a model for amyotrophic lateral sclerosis caused by SOD1 mutation. Suppression of the p53 checkpoint response and protection against DNA damage are proposed as the underlying neuroprotective mechanisms. These findings provide insights into fundamental mechanisms involved in p25/cdk5 pathology and neurodegeneration in general, and suggest novel therapeutic strategies for Alzheimer's disease, stroke, and other disorders. A panoptic model is proposed where multiple neurotoxic signaling events involving p25/cdk5 converge at the level of DNA damage to incite dysfunction and death in neurons.