TY - JOUR
T1 - Toxicity Inhibitors Protect Lipid Membranes from Disruption by Aβ42
AU - Malishev, Ravit
AU - Nandi, Sukhendu
AU - Kolusheva, Sofiya
AU - Levi-Kalisman, Yael
AU - Klärner, Frank Gerrit
AU - Schrader, Thomas
AU - Bitan, Gal
AU - Jelinek, Raz
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/10/28
Y1 - 2015/10/28
N2 - Although the precise molecular factors linking amyloid β-protein (Aβ) to Alzheimer's disease (AD) have not been deciphered, interaction of Aβ with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting Aβ have focused on interfering with Aβ self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of Aβ42, the longer form of Aβ, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment Aβ(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLR01, all of which previously were shown to disrupt different steps in Aβ42 self-assembly. Biophysical experiments revealed that incubation of Aβ42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLR01 were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with Aβ42, suggesting that binding of the assembly modulators to the peptide attenuated their membrane interactions. Importantly, our study reveals that even though the three tested compounds affect Aβ42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with Aβ42, suggesting that preventing the interaction of Aβ42 with the membrane contributes substantially to inhibition of its toxicity by each compound. The data suggest that interference with membrane interactions is an important factor for Aβ42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.
AB - Although the precise molecular factors linking amyloid β-protein (Aβ) to Alzheimer's disease (AD) have not been deciphered, interaction of Aβ with cellular membranes has an important role in the disease. However, most therapeutic strategies targeting Aβ have focused on interfering with Aβ self-assembly rather than with its membrane interactions. Here, we studied the impact of three toxicity inhibitors on membrane interactions of Aβ42, the longer form of Aβ, which is associated most strongly with AD. The inhibitors included the four-residue C-terminal fragment Aβ(39-42), the polyphenol (-)-epigallocatechin-3-gallate (EGCG), and the lysine-specific molecular tweezer, CLR01, all of which previously were shown to disrupt different steps in Aβ42 self-assembly. Biophysical experiments revealed that incubation of Aβ42 with each of the three modulators affected membrane interactions in a distinct manner. Interestingly, EGCG and CLR01 were found to have significant interaction with membranes themselves. However, membrane bilayer disruption was reduced when the compounds were preincubated with Aβ42, suggesting that binding of the assembly modulators to the peptide attenuated their membrane interactions. Importantly, our study reveals that even though the three tested compounds affect Aβ42 assembly differently, membrane interactions were significantly inhibited upon incubation of each compound with Aβ42, suggesting that preventing the interaction of Aβ42 with the membrane contributes substantially to inhibition of its toxicity by each compound. The data suggest that interference with membrane interactions is an important factor for Aβ42 toxicity inhibitors and should be taken into account in potential therapeutic strategies, in addition to disruption or remodeling of amyloid assembly.
KW - Molecular tweezer
KW - amyloid β-protein (Aβ)
KW - fibril inhibitors
KW - membrane interactions
KW - polyphenols
UR - http://www.scopus.com/inward/record.url?scp=84947793747&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.5b00200
DO - 10.1021/acschemneuro.5b00200
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C2 - 26317327
AN - SCOPUS:84947793747
SN - 1948-7193
VL - 6
SP - 1860
EP - 1869
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 11
ER -