| Cyclin-dependent kinase 5 (Cdk5) is a proline-directed Ser/Thr kinase with diverse roles in the nervous system, including neuronal migration, neurite development, neurotransmission, cognition, synaptic plasticity and neurodegeneration. Cdk5 is activated upon binding to one of its two activators, p35 or p39. Aberrant activation of Cdk5 can occur through the proteolytic cleavage of p35 to p25 via calpain, a calcium-dependent cysteine protease. Generation of p25 is associated with neurotoxicity and neurodegeneration. The forebrain-specific CK-p25 inducible mouse model of p25 overexpression exhibits progressive neuronal death, reduced synaptic plasticity, and impaired learning following p25 overexpression in the forebrain. Levels of Abeta, as well as beta-secretase (BACE1), are also increased in CK-p25 mice. In my dissertation research, I found that partial genetic deletion of BACE1 reduces Abeta close to wild-type levels in the CK-p25 mouse and that expression of a single copy of BACE1 rescued synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated by the reduction in BACE1 levels. These findings led us to propose that Abeta primarily drives the cognitive impairment, and synapse loss and dysfunction present in the CK-p25 mice, while the p25/Cdk5 complex, through other targets, is mainly responsible for the neuronal death and neurodegeneration.;Until now cleavage of p35 into p25 has only been observed with neurotoxic insults. As part of my dissertation research I also found that diverse physiological stimuli are able to generate p25. Long-term potentiation (LTP) is believed to be a cellular correlate of learning and memory. My work demonstrates that chemical LTP induction protocols generate p25 in cultured neurons without resulting in cell death. Interestingly, the generation of p25 seems to be dependent on NMDA function and CaMKII activity. My results suggest that p25 may be generated under physiological conditions reminiscent of LTP.;To characterize the independent functions of p35/Cdk5 and p25/Cdk5 in vivo, I developed a knock-in mouse expressing a cleavage-resistant p35 (Deltap35KI). The Deltap35KI are viable and fertile and do not exhibit any outward phenotype when examined in a number of behavioral paradigms. This new mouse model will allow us to examine the physiological and pathological consequences of p25 production in vivo. Importantly, this model will allow us to take an alternative approach to studying cellular and molecular mechanisms of neurodegeneration, and to test the hypothesis that pathological p25 generation is crucial for neurodegeneration. |
