Amyloid pores formation

Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J. Interaction of Alzheimer s beta-amyloid peptides with cholesterol mechanistic insights into amyloid pore formation. Biochemistry. 2014 53(28) 4489-4502. 

Once these control experiments were performed, we could evaluate the capacity of bexarotene to block the formation of amyloid pores induced by Ap peptides. In these experiments, SH-SY5Y cells were treated with Ap25-35 (or Api-42) in presence of bexarotene (molar ratio 1 1). Under these conditions, we did not detect any increase of Ca fluxes (Fig. 14.12A, right panel). This effect was observed not only when bexarotene and Ap25-35 were premixed for 1 h before addition to the cells but also when both compoxmds were simultaneous added into the cells. Finally, we demonstrated that bexarotene can inhibit the elevation of Ca entry induced by Api-42 (Fig. 14.12B-C). The photomicrographs taken during the experiments indicated that the inhibitory effect of bexarotene was xmiformly distributed over the cell culture (Fig. 14.12B). Overall, tiiese data show that bexarotene is a potent blocker of amyloid pore formation. 

Hirakura, Y., and Kagan, B. L. (2001). Pore formation by beta-2-microglobulin A mechanism for the pathogenesis of dialysis associated amyloidosis. Amyloid 8, 94-100. 

FIGURE 8.6 Pore formation by amyloid proteins a membrane-assisted process. Amyloid proteins that have acquired an a-helical structure upon binding to Kpid rafts can penetrate the membrane. The presence of cholesterol rmderneath the glycosphingoHpids (GSL) in lipid raft areas stimulates both the insertion of the protein within the membrane and its oligomerization into Ca -permeable pores. 

The other possibility for the formation of an amyloid pore is the insertion of Ap monomers in the membrane, which could be followed by an oligomerization process inside the membrane. Like a-S5muclein, Ap is constrained to adopt an a-helical structure when boimd to lipids. Thus, tiie first step in the formation of an a-structured Ap pore is the interaction of Ap with selected membrane lipids (e.g., ganglioside GMl, which is concentrated in lipid raft domains). In this case, Ap will readily adopt an a-helical conformation (Fig. 11.4). The insertion of a-helical Ap may require the involvement of additional lipids, such as cholesterol, which will also promote the oligomerization process leading to the formation of a functional Ca -permeable pore. As noted by Jang et the a-helical structure of Ap is first formed on the membrane surface. Thus, the insertion of a-helical Ap may require an enei input that can be furnished by the interaction of Ap with cholesterol. In this respect, it is clear ftat the formation of an a-helical oligomeric pore of Ap is strictly dependent upon the presence of specific lipids, especially cholesterol, in the plasma membrane of brain cells. 

Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T., and Lansbury, P. T., Jr. (2002). Alpha-synuclein, especially the Parkinson s disease-associated mutants, forms pore-like annular and tubular protofibrils./. Mol. Biol. 322,1089-1102. LeVine, H. (1993). Thioflavine T interaction with synthetic Alzheimer s disease beta-amyloid peptides Detection of amyloid aggregation in solution. Protein Sci. 2, 404—410. Lin, H., Bhatia, R., and Lai, R. (2001). Amyloid beta protein forms ion channels Implications for Alzheimer s disease pathophysiology. FASEB J. 15, 2433-2444. Lorenzo, A., and Yankner, B. A. (1994). Beta-amyloid neurotoxicity requires fibril formation and is inhibited by Congo red. Proc. Natl. Acad. Sci. USA 91, 12243-12247. Luhrs, T., Ritter, C., Adrian, M., Riek-Loher, D., Bohrmann, B., Dobeli, H., Schubert, D., and Riek, R. (2005). 3D structure of Alzheimer s amyl o id-( be la) (1—12) fibrils. Proc. Natl. Acad. Sci. USA 102, 17342-17347. 

---