Neurodegeneration and Neuroinflammation in cdk5/p25-Inducible Mice

Abstract

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 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.

AAV-Tau Mediates Pyramidal Neurodegeneration by Cell-Cycle Re-Entry without Neurofibrillary Tangle Formation in Wild-Type Mice

“…These features closely resembled degenerating hippocampal neurons in our mice that model hippocampal sclerosis by inducible expression of p25, the truncated activator of cdk5 [28]. Other pathological features like tangles, spheroids and axonal dilatations were revealed by various staining methods, but only sporadically and not consistently in all AAV-Tau injected mice (Figure S6D).…”

Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease

“…Previously, we have observed a similar relation of microgliosis to neurodegeneration in an unrelated model for hippocampal sclerosis, caused by conditional expression of p25, the truncated activator of cdk5 [39]. Also, in that model, intense neurodegeneration was not marked by aggregation of protein Tau, further strengthening our conclusion that cdk5 is not a major Tau-kinase in vivo [39–41]. …”

“…Degenerating neurons in the AAV-Tau.P301L injected mice displayed as dark neurons with extensive vacuolization that could be taken to indicate a defective autophagic process. A similar facet of neurons we observed in an unrelated mouse model, that is, the p25 inducible mice that recapitulate hippocampal sclerosis [39]. The combined data do lend more support to the hypothesis that vacuolization is a correlate or consequence of the degenerative process, as an intrinsic mechanism needed to clean up defective organelles, protein aggregates or even entire dead or dying neurons.…”

TFP5, a Peptide Derived from p35, a Cdk5 Neuronal Activator, Rescues Cortical Neurons from Glucose Toxicity

“…This seems to be the case in p25 transgenic mice which respond initially to p25 overexpression with Cdk5 hyperactivation, neuroinflammation (astrogliosis microgliosis), tau hyperphosphorylation, amyloidgenesis, and an AD behavioral phenotype [36, 37]. A novel biochemical pathway for cdk5/p25-induced neuroinflammation has been proposed to explain the results of p25 overexpression in these transgenic mice [37].…”