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

Abstract

The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD). In particular, p25/Cdk5 has been shown to produce hyperphosphorylated tau, neurofibrillary tangles as well as aberrant amyloid precursor protein processing found in AD. Neuroinflammation has been observed alongside the pathogenic process in these neurodegenerative diseases, however the precise mechanism behind the induction of neuroinflammation and the significance in the AD pathogenesis has not been fully elucidated. In this report, we uncover a novel pathway for p25-induced neuroinflammation where p25 expression induces an early trigger of neuroinflammation in vivo in mice. Lipidomic mass spectrometry, in vitro coculture and conditioned media transfer experiments show that the soluble lipid mediator lysophosphatidylcholine (LPC) is released by p25 overexpressing neurons to initiate astrogliosis, neuroinflammation and subsequent neurodegeneration. Reverse transcriptase PCR and gene silencing experiments show that cytosolic phospholipase 2 (cPLA2) is the key enzyme mediating the p25-induced LPC production and cPLA2 upregulation is critical in triggering the p25-mediated inflammatory and neurodegenerative process. Together, our findings delineate a potential therapeutic target for the reduction of neuroinflammation in neurodegenerative diseases including AD.

Novel Phospholipid Signature of Depressive Symptoms in Patients With Coronary Artery Disease

“…Phospholipase A2 (PLA2) converts erythrocyte PC and PS into lysophospholipids that readily leave the membrane to function as regulatory messengers 39. Lyso‐PC released from glial cells initiate neurodegenerative processes through inflammatory cascades 40. Likewise, activated platelets, a common feature in CAD, catalyze the deacylation of PS into lyso‐PS 41.…”

Peptides Derived from Neuronal Cell Cycle like Kinase 5 Activator p35, in Neurodegeneration; Pathology and Therapy

“…It should be noted, in this transgenic, up regulation of p25 and hyperactivity of Cdk5 initiate inflammation via phosphorylation and activation of neuronal phospholipase 2A followed by astroglyosis and microgliosis which precede Abeta accumulation and tau phosphorylation [19]. In fact the situation has become even more confounding with the mixed results from other p25 mouse transgenic initiated at fertilization [22,23].…”

“…In the earlier study most data were reported after 5-12 weeks of induction and showed upregulation of Cdk5/p25 activity correlated with tau phosphorylated aggregates, a neurofibrillary pathology [17]. A later study recorded earlier time points with Cdk5 activation evident after one week induction [19]. Virtually at the same time, inflammatory signs were seen with an uptick of GFAP at one week, cytokines and chemokines of microgliosis and phosphor-tau after 4 weeks induction, followed by Abeta, most evident at 8 weeks post induction.…”

“…Conception, development and post-natal growth (at least to 12 days) are normal in the presence of doxycycline whereas removal of doxycycline induced over-expression of cortical p25, increased Cdk5 activity, neuronal loss, and progression to an AD-like phenotype with Ab plaques, hyper-phosphorylated tau tangles and inflammation [17,19]. It should be noted, in this transgenic, up regulation of p25 and hyperactivity of Cdk5 initiate inflammation via phosphorylation and activation of neuronal phospholipase 2A followed by astroglyosis and microgliosis which precede Abeta accumulation and tau phosphorylation [19].…”

“…In addition to cytoskeletal protein hyperphosphorylation, Cdk5/p25 hyperphosphorylation of other enzymes such as mitochondrial and other metabolic enzymes activities also affected and to enhance toxic effects. Perhaps the best example of p25-induced toxicity and progression of the AD phenotype is the p25 transgenic model mouse (p25Tg) [17,19,20] revealed all the AD phenotypes. We used bitransgenic (CK-p25Tg) mice (males and females) in which forebrain CK-p25 expression was tightly regulated by the tet on/off system facilitated by the CamKII (CK) promoter [17].…”