title: 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.
authors.affiliation: Neurobiology and Ageing Program, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456.
authors.forename: Jeyapriya R
authors.initials: JR
authors.lastname: Sundaram
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Chan
authors.forename: Charlene P
authors.initials: CP
authors.lastname: Poore
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pareek
authors.forename: Wei Fun
authors.initials: WF
authors.lastname: Cheong
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.forename: Ning
authors.initials: N
authors.lastname: Tang
authors.forename: Chian-Ming
authors.initials: CM
authors.lastname: Low
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.forename: Sashi
authors.initials: S
authors.lastname: Kesavapany
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000494:pharmacology*; D010770:Phosphotransferases; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C492236:Cdk5r1 protein, mouse; D017077:Culture Media, Conditioned; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008244:Lysophosphatidylcholines; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D054510:Phospholipases A2, Cytosolic