Role of membrane GM1 on early neuronal membrane actions of A β during onset of Alzheimer's disease

In this study, we examined if the association and subsequent membrane perforation induced by Aβ was dependent on GM1 levels. Pretreatment of hippocampal neurons with D-PDMP decreased GM1 and Aβ clustering at the membrane (Aβ fluorescent-punctas/20μm, control=16.2±1.1 vs. D-PDMP =6.4±0.4, p <0.001). Interestingly, membrane perforation with Aβ occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control=7.8±2 vs. low GM1=12.1±0.5, p <0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by Aβ. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control=7.8±2 vs. GM1=6.2±1min, p <0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of Aβ with GM1, attenuated membrane perforation significantly. Furthermore, pretreatment with CTB decreased the membrane association of Aβ (fluorescent-punctas/20μm, Aβ: control=14.8±2.5 vs. CTB=8±1.4, p <0.05), suggesting that GM1 also plays a role in both association of Aβ with the membrane and in perforation. In addition, blockade of the Aβ association with CTB inhibited synaptotoxicity. Taken together, our results strongly suggest that membrane lipid composition can affect the ability of Aβ to associate and subsequently perforate the plasma membrane thereby modulating its neurotoxicity in hippocampal neurons...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research