Aberrant Cdk5 Activation by p25 Triggers Pathological Events Leading to Neurodegeneration and Neurofibrillary Tangles

Abstract

Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…106 Overexpression of p25 in a rodent model resulted in increased tau phosphorylation and neurodegeneration and SP/TP phosphorylation by cdk5 increased tau toxicity in a Drosophila fruit fly model. 71,107,108 Recent evidence suggests that cdk5/p25 might be a downstream effector of A␤ mediated toxicity, leaving cdk5 as a promising therapeutic target. 109 One must be aware, however, that the inhibition of cdk5 was accompanied by activation of GSK-3␤ in neuronal cell culture and that p35 knock-out mice revealed increased GSK-3␤ activity and tau phosphorylation.…”

The Involvement of Cdk5 Activator p35 in Social Isolation-Triggered Onset of Early Alzheimer’s Disease-Related Cognitive Deficit in the Transgenic Mice

“…p35 has a short cellular half-life and its degradation leads to aberrant activation of p25/Cdk5, which induces tau phosphorylation and contributes directly to the pathogenesis of AD (Patrick et al, 1999;Noble et al, 2003). In a mouse model of AD, prolonged expression of p25 induced by an inducible transgenic system or by lipopolysaccharide resulted in hyperphosphorylation of tau and severe neurodegeneration (Cruz et al, 2003;Fischer et al, 2005;Kitazawa et al, 2005). The purpose of this study was to elucidate the mechanism of how social isolation accelerated the decline of memory in the APP/PS1 mice.…”

Autocatalytic Phosphorylation of CDK2 at the Activating Thr160

“…Although the vast majority of CDKs play a distinctive role in controlling the eukaryotic cell cycle and thus cellular proliferation, some have been shown to play a role in other physiological processes such as transcriptional regulation, 1 neuronal development 2,3 and apoptosis. 4 Multiple regulatory mechanisms have evolved to tightly control the activity of this important class of enzymes.…”