title: An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling.
abstract: Many neurodegenerative diseases present the loss of synapses as a common pathological feature. Here we have employed an in vitro model for synaptic loss to investigate the molecular mechanism of a therapeutic treatment, valproic acid (VPA). We show that amyloid-β (Aβ), isolated from patient tissue and thought to be the causative agent of Alzheimer's disease, caused the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine-string protein from cultured mouse neurons. Aβ-induced synapse damage was reduced by pre-treatment with physiologically relevant concentrations of VPA (10 μM) and a structural variant propylisopropylacetic acid (PIA). These drugs also reduced synaptic damage induced by other neurodegenerative-associated proteins α-synuclein, linked to Lewy body dementia and Parkinson's disease, and the prion-derived peptide PrP82-146. Consistent with these effects, synaptic vesicle recycling was also inhibited by these proteins and protected by VPA and PIA. We show a mechanism for this damage through aberrant activation of cytoplasmic phospholipase A2 (cPLA2) that is reduced by both drugs. Furthermore, Aβ-dependent cPLA2 activation correlates with its accumulation in lipid rafts, and is likely to be caused by elevated cholesterol (stabilising rafts) and decreased cholesterol ester levels, and this mechanism is reduced by VPA and PIA. Such observations suggest that VPA and PIA may provide protection against synaptic damage that occurs during Alzheimer's and Parkinson's and prion diseases.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK.
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
authors.affiliation: Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK. Electronic address: cbate@rvc.ac.uk.
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D021962:Membrane Microdomains / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism*; D011328:Prions / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D050987:Vesicle-Associated Membrane Protein 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011328:Prions; D016708:Synaptophysin; D050987:Vesicle-Associated Membrane Protein 1; C075222:amyloid beta-protein (1-42); C088460:cysteine string protein; D015759:Ionomycin; D014635:Valproic Acid; D002784:Cholesterol; D054467:Phospholipases A2
keywords: Alzheimer's; Neurodegeneration; Parkinson's; Phospholipase A(2); Prion; Synapse