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.
Highlights
Neurodegenerative diseases comprise a disparate group of conditions involving a common loss of synaptic function
We further demonstrate that this mechanism of Aβinduced toxicity is associated with increased translocation of cytoplasmic phospholipase A2 (cPLA2) to lipid rafts, since Aβ causes a dose-dependent increase in cholesterol and a reduction in cholesterol esters, and that this process is reduced by valproic acid (VPA) and propylisopropylacetic acid (PIA)
In this study we demonstrate that VPA and PIA protected cultured neurons against synapse damage induced by the neurotoxic peptides Aβ, PrP82-146 and αSN
Summary
Neurodegenerative diseases comprise a disparate group of conditions involving a common loss of synaptic function. These conditions provide a huge societal impact, with a large number of people experiencing severe symptoms. Alzheimer’s disease is amongst the most important of these diseases, where the progressive loss of neuronal function is associated with the production of neurotoxic amyloid-β (Aβ) peptides that are cleaved from the C terminal of the amyloid precursor protein (Hardy, 2006). The clinical symptoms in Alzheimer’s disease are caused by the loss or dysfunction of synapses (Walsh and Selkoe, 2004), and the best correlate of the degree of dementia in Alzheimer’s disease patients is a reduction in synaptic density and the loss of synaptic proteins including synaptophysin, cysteine-string protein (CSP), vesicle-associated membrane protein (VAMP)-1 and synapsin-1 (Reddy et al, 2005; Terry et al, 1991).
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