期刊
NEUROPHARMACOLOGY
卷 101, 期 -, 页码 225-236出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.09.030
关键词
Alzheimer's disease; Amyloid-beta; Glimepiride; Glycosylphosphatidylinositols; Phospholipase A(2); Prion; Synapses; Synaptophysin
资金
- European Commission FP6 Neuroprion - Network of Excellence
- Royal Veterinary College
Alzheimer's disease is associated with the accumulation within the brain of amyloid-beta (A beta) peptides that damage synapses and affect memory acquisition. This process can be modelled by observing the effects of A beta on synapses in cultured neurons. The addition of picomolar concentrations of soluble A beta derived from brain extracts triggered the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine string protein from cultured neurons. Glimepiride, a sulphonylurea used for the treatment of diabetes, protected neurons against synapse damage induced by A beta. The protective effects of glimepiride were multi-faceted. Glimepiride treatment was associated with altered synaptic membranes including the loss of specific glycosylphosphatidylinositol (GPI)-anchored proteins including the cellular prion protein (PrPC) that acts as a receptor for A beta(42), increased synaptic gangliosides and altered cell signalling. More specifically, glimepiride reduced the A beta-induced increase in cholesterol and the A beta-induced activation of cytoplasmic phospholipase A(2) (cPLA(2)) in synapses that occurred within cholesterol-dense membrane rafts. A beta(42) binding to glimepiride-treated neurons was not targeted to membrane rafts and less A beta(42) accumulated within synapses. These studies indicate that glimepiride modified the membrane micro-environments in which A beta-induced signalling leads to synapse damage. In addition, soluble PrPC, released from neurons by glimepiride, neutralised A beta-induced synapse damage. Such observations raise the possibility that glimepiride may reduce synapse damage and hence delay the progression of cognitive decline in Alzheimer's disease. (C) 2015 Elsevier Ltd. All rights reserved.
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