|کد مقاله||کد نشریه||سال انتشار||مقاله انگلیسی||ترجمه فارسی||نسخه تمام متن|
|5548695||1556589||2018||9 صفحه PDF||سفارش دهید||دانلود کنید|
- Valproic acid (VPA) and propylisopropylacetic acid (PIA) affect soluble AÎ² species in 7PA2 cells.
- VPA and PIA reduced release of soluble AÎ² oligomers from 7PA2 cells.
- VPA and PIA increased release of AÎ² monomers from 7PA2 cells.
- Platelet activating factor reversed the effects of VPA and PIA on AÎ² species in 7PA2 cells.
The amyloid hypothesis of Alzheimer's disease suggests that synaptic degeneration and pathology is caused by the accumulation of amyloid-Î² (AÎ²) peptides derived from the amyloid precursor protein (APP). Subsequently, soluble AÎ² oligomers cause the loss of synaptic proteins from neurons, a histopathological feature of Alzheimer's disease that correlates with the degree of dementia. In this study, the production of toxic forms of AÎ² was examined inÂ vitro using 7PA2 cells stably transfected with human APP. We show that conditioned media from 7PA2 cells containing AÎ² oligomers caused synapse degeneration as measured by the loss of synaptic proteins, including synaptophysin and cysteine-string protein, from cultured neurons. Critically, conditioned media from 7PA2 cells treated with valproic acid (2-propylpentanoic acid (VPA)) or propylisopropylacetic acid (PIA) did not cause synapse damage. Treatment with VPA or PIA did not significantly affect total AÎ²42 concentrations; rather these drugs selectively reduced the concentrations of AÎ²42 oligomers in conditioned media. In contrast, treatment significantly increased the concentrations of AÎ²42 monomers in conditioned media. VPA or PIA treatment reduced the concentrations of APP within lipid rafts, membrane compartments associated with AÎ² production. These effects of VPA and PIA were reversed by the addition of platelet-activating factor, a bioactive phospholipid produced following activation of phospholipase A2, an enzyme sensitive to VPA and PIA. Collectively these data suggest that VPA and PIA reduce AÎ² oligomers through inhibition of phospholipase A2 and suggest a novel therapeutic approach to Alzheimer's treatment.
Journal: Neuropharmacology - Volume 128, January 2018, Pages 54-62