Conditional Deletion of Neuronal Cyclin-Dependent Kinase 5 in Developing Forebrain Results in Microglial Activation and Neurodegeneration

Abstract

Neuronal migration disorders are often identified in patients with epilepsy refractory to medical treatment. The prolonged or repeated seizures are known to cause neuronal death; however, the mechanism underlying seizure-induced neuronal death remains to be elucidated. An essential role of cyclin-dependent kinase 5 (Cdk5) in brain development has been demonstrated in Cdk5(-/-) mice, which show neuronal migration defects and perinatal lethality. Here, we show the consequences of Cdk5 deficiency in the postnatal brain by generating Cdk5 conditional knockout mice, in which Cdk5is selectively eliminated from neurons in the developing forebrain. The conditional mutant mice were viable, but exhibited complex neurological deficits including seizures, tremors, and growth retardation. The forebrain not only showed disruption of layering, but also neurodegenerative changes accompanied by neuronal loss and microglial activation. The neurodegenerative changes progressed with age and were accompanied by up-regulation of the neuronal tissue-type plasminogen activator, a serine protease known to mediate microglial activation. Thus age-dependent neurodegeneration in the Cdk5 conditional knockout mouse brain invoked a massive inflammatory reaction. These findings indicate an important role of Cdk5 in inflammation, and also provide a mouse model to examine the possible involvement of inflammation in the pathogenesis of progressive cognitive decline in patients with neuronal migration disorders.

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

“…The loss of Cdk5 activity (Takahashi et al, 2010) and hyperactivation of Cdk5 (Kitazawa et al, 2005) lead to neuronal loss and in either situation neuroinflammation has been reported to be one key biochemical event linked with this process. However, the molecular mechanism behind hyperactivation of Cdk5, and its relevance to neurodegenerative disease pathogenesis has not been elucidated.…”

“…2 B). Previous studies reported that microglial activation can be induced by neuronal tissue plasminogen activator (tPA), a serine protease that catalyzes the conversion of inactive plasminogen to the active protease plasmin (Takahashi et al, 2010). To study the role of tPA in the microglial activation, we have also performed the immunohistochemistry with tPA antibody.…”

The Roles of Cdk5-Mediated Subcellular Localization of FOXO1 in Neuronal Death

“…One mechanism by which the hyperactivation of Cdk5 might occur is through the proteolytic cleavage of p35 by the calcium-dependent protease calpain to create p25. This cleavage is prominent in the neuronal response to ␤-amyloid-induced stress (Patrick et al, 1999;Su and Tsai, 2011). Although too much Cdk5 activity might be bad, too little Cdk5 is also dangerous to the health and survival of adult neurons.…”

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…Rather, Cdk5 interacts with its obligate partner proteins, p35 and p39, [10][11][12][13] whose constitutive expression in postmitotic neurons is essential for the many known functions of Cdk5 in the regulation of cytoarchitecture, synaptic function, and dopamine signaling in the central nervous system. Physiologic Cdk5 activity is essential in neuronal development, [14][15][16][17] memory, and neurogenesis, 16 whereas aberrant hyperactivity of Cdk5 has been linked with neurodegenerative disorders 11,[18][19][20][21] Data from our laboratory and others have implicated Cdk5 in immune dysregulation 13,22,23 and inflammatory pain signaling activated by tumor necrosis factor a (TNFa) through mechanisms that include transcriptional upregulation of p35. 24,25 We recently demonstrated a role for Cdk5 in posttranslational modification of proteins triggered by T-cell receptor (TCR) and chemokine receptor signaling and required for optimal immune synapse formation, cellular activation, and migratory capacity.…”