The cyclin-dependent kinase 5(CDK5)activators,p35 and p25,have a proposed role in the pathogenesis of neurodegenerative disorders.We have recently shown that glycogen synthase kinase 3β(GSK3β)also binds to p25(but not p35).When it does so,GSK3β hyperphosphorylates tau; yet the phosphorylation of β-catenin is reduced,increasing its stability.This stabilized β-catenin increases in the cell nucleus and should protect neurons from apoptosis.Intrigued by observations that tangle-free neurons close to tangle-bearing neurons display degenerative morphologies and markers,we hypothesized that the tangle-bearing neurons,though themselves protected from cell death,might produce a factor that damaged otherwise healthy cells nearby.To test this idea we analyzed the bi-transgenic CK-p25 Tg mouse in which the expression of p25 is under the control of CamKII promoter and can be switched on or off with doxycycline.After inducing p25 expression for 8 weeks,we found that neurons in frontal cortex showed robust p25 expression and these cells had enhanced nuclear β-catenin.We found a one-third increase in the number of cleaved caspase-3 positive neurons,yet only half of these cells were also GFP-p25 positive.Intriguingly,nearby neurons with limited induction of GFP-p25(and low levels of nuclear β-catenin),showed substantially elevated cell death markers.We observed the same phenomenon in vitro; cleaved caspase-3+ N2a cells or primary cortical neurons were significantly more frequent in close proximity to cells ectopically expressing p25; nuclear β-catenin was not present in the majority of these cells.A possible mechanism for this result is that Notum-a secreted Wnt antagonist and a β-catenin downstream target-was significantly elevated in conditioned medium from p25-overexpressing cells.Notum immunostaining was also elevated in brain sections of CK-p25 Tg mice.Our findings suggest that persistent aberrant activation of β-catenin by p25-expressing neurons triggers a trans-neuronal inhibition of Wnt signaling by Notum that leads in turn to the degeneration of p25/tangle-free neurons.The existence of this neuron-killing-neuron scenario has significant implications for our understanding of neurodegenerative disease.