The cyclin-dependent kinase cdk5 is atypically active in postmitotic neurons and enigmatic among the kinases proposed as molecular actors in neurodegeneration. We generated transgenic mice to express p25, the N-terminally truncated p35 activator of cdk5, in forebrain under tetracycline control (TET-off). Neuronal expression of p25 (p25) caused high mortality postnatally and early in life. Mortality was completely prevented by administration of doxycycline in the drinking water of pregnant dams and litters until P42, allowing us to study the action of p25 in adult mouse forebrain. Neuronal p25 triggered neurodegeneration and also microgliosis, rapidly and intensely in hippocampus and cortex. Progressive neurodegeneration was severe with marked neuron loss, causing brain atrophy (40% loss at age 5 months) with nearly complete elimination of the hippocampus. Neurodegeneration did not involve phosphorylation of protein tau or generation of amyloid peptide. Degenerating neurons did not stain for terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling or activated caspase-3 but were marked by FluoroJadeB in early stages. Diseased neurons were always closely associated with activated microglia already very early in the disease process. Primary neurons derived from p25 embryos were more prone to apoptosis than wild-type neurons, and they activated microglial cells in co-culture. The inducible p25 mice present as a model for neurodegeneration in hippocampal sclerosis and neocortical degeneration, with important contributions of activated microglia. (Am J Pathol 2008, 172:470–485; DOI: 10.2353/ajpath.2008.070693) Among the cyclin-dependent kinases, cdk5 is not typical because it is not directly involved in cell cycle control. Rather, cdk5 is specifically active in postmitotic neurons and can be regarded as negatively controlling or even blocking their cycling. The catalytic subunit of cdk5 is widely expressed, but its obligate activating subunits are expressed almost exclusively in brain in postmitotic neurons. Cdk5 is best known for its role in development in the cortical layering, which is disturbed in cdk5 / mice, causing embryonic lethality, similar to reeler mice. On the other hand, perinatal abrogation of cdk5 reduces embryonic lethality although cortical layer defects remain, thereby dissociating both phenomena. Proper kinase activity of cdk5 requires heterodimer formation with neuronal activators p35 or p39, whereas in pathological circumstances, N-truncated derivatives p25 and p29 have been identified. Mice lacking p35 are viable with only minor problems of corticogenesis, whereas p39-deficient mice are normal. Combined p35/ p39 deficiency was lethal similar to cdk5 / , and the combined data demonstrate that p35 is the dominant activator of cdk5 in neurons.