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(ON)) 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 nick-end 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.