Amyloid pores

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. 

Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, et al. Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. / Neurochem. 2006 97(4) 1071-1077. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury Jr PT. Neurodegenerative disease amyloid pores from pathogenic mutations. Nature. 2002 418(6895) 291. 

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. 

FIGURE 11.8 How a-helical Api-42 bound to both GMl and cholesterol can form a Ca -permeable amyloid pore. The topology of A(51-42 constrained by both GMl and cholesterol is the same as in Fig. 11.7B. Note that once bound to A(51-42, GMl and cholesterol determine the orientation of Ap inside the membrane. His-13, located at the pore mouth, may attract Ca ions in the channel. The interaction of 7x ions with these residues blocks the channel. 

Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury Jr PT. Neurodegenerative disease amyloid pores from pathogenic mutations. Nature. 2002 418(6895) 291. 

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. 

Amyloid pore An oligomer of amyloid proteins that forms a channel, generally permeable to calcium ions, in the plasma membrane of brain cells in patients with neurodegenerative diseases. Pore oligomers are considered as the more toxic forms of amyloid proteins. 

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