Axonopathy, tau abnormalities, and dyskinesia, but no neurofibrillary tangles in p25‐transgenic mice

Abstract

Neurofibrillary tangles, one of the pathologic hallmarks of Alzheimer's disease (AD), are composed of abnormally polymerized tau protein. The hyperphosphorylation of tau alters its normal cellular function and is thought to promote the formation of neurofibrillary tangles. Growing evidence suggests that cyclin-dependent kinase 5 (cdk5) plays a role in tau phosphorylation, but the function of the enzyme in tangle formation remains uncertain. In AD, cdk5 is constitutively activated by p25, a highly stable, 25kD protein thought to be increased in the AD brain. To test the hypothesis that p25/cdk5 interactions promote neurofibrillary pathology, we created transgenic mouse lines that overexpress the human p25 protein specifically in neurons. Mice with high transgenic p25 expression have augmented cdk5 activity and develop severe hindlimb semiparalysis and mild forelimb dyskinesia beginning at approximately 3 months of age. Immunohistochemical and ultrastructural analyses showed widespread axonal degeneration with focal accumulation of tau in various regions of the brain and, to a lesser extent, the spinal cord. However, there was no evidence of neurofibrillary tangles in neuronal somata or axons, nor were paired helical filaments evident ultrastructurally. These studies confirm that p25 overexpression can lead to tau abnormalities and axonal degeneration in vivo but do not support the hypothesis that p25-related induction of cdk5 is a primary event in the genesis of neurofibrillary tangles.

Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5

“…Thus, neurotoxicity induced by ␤-amyloid, ischemia, or MPTP causes aberrant Cdk5 activity through the generation and accumulation of p25 (Cruz and Tsai, 2004;Dhariwala and Rajadhyaksha, 2008). Furthermore, this truncated p25 form relocalizes Cdk5 activity with the consequent alteration of Cdk5 substrate specificity (Patrick et al, 1999;Ko et al, 2001;Bian et al, 2002). Actually, elevated Cdk5 activity accumulation of p25 and hyperphosphorylated tau have been described in brain of AD patients (Cruz and Tsai, 2004;Dhariwala and Rajadhyaksha, 2008).…”

p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death

“…Furthermore, the p25-Cdk5 complex was shown to be harmful to neurons, as evidenced by cytoskeleton disruption, neuritic retraction and expression of apoptotic markers (Ahlijanian et al, 2000;Bian et al, 2002;Patrick et al, 1999;Hamdane et al, 2003a). Interestingly, deregulation of Cdk5 activity by association with its activator p25 is likely to be involved in AD pathogenesis (Lee et al, 1999;Patrick et al, 1999;Patrick et al, 2001;Cruz et al, 2003;Noble et al, 2003).…”

Cdk5/p25-Induced Cytosolic PLA2-Mediated Lysophosphatidylcholine Production Regulates Neuroinflammation and Triggers Neurodegeneration

“…Increased levels of p25 protein have also been found in the postmortem brain tissue of AD patients (Patrick et al, 1999;Tseng et al, 2002). Although this has been debated by a number of groups (Takashima et al, 2001;Bian et al, 2002), the proteolytic cleavage of p35 to p25, which has been shown to hyperactivate Cdk5 is without doubt. Deregulation of Cdk5 activity, accompanied by the accumulation of p25 has been implicated as a causative factor in the pathogenesis of neurodegenerative diseases (Nguyen et al, 2001;Smith et al, 2006).…”