TY - JOUR
T1 - Macrocyclic Peptides Derived from Familial Alzheimer's Disease Mutants Show Charge-Dependent Oligomeric Assembly and Toxicity
AU - Howitz, William J.
AU - Guaglianone, Gretchen
AU - McKnelly, Kate J.
AU - Haduong, Katelyn
AU - Ashby, Shareen N.
AU - Laayouni, Mohamed
AU - Nowick, James S.
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/3/16
Y1 - 2022/3/16
N2 - This work probes the role of charge in the oligomeric assembly, toxicity, and membrane destabilization of a series of peptides derived from Aβ and the E22Q and E22K familial mutants. In the mutant Aβ peptides, an acidic residue (E) is replaced with either a neutral or basic residue (Q or K), thus altering the net charge of the peptide. Acetylation at peripheral positions permits modulation of charge of the peptides and allows investigation of the role of charge in their oligomeric assembly, cytotoxicity, and membrane disruption. Peptides with the same net charge generally behave similarly even if the amino acid residue at position 22 differs. As the net charge of the peptide decreases, so does the extent of assembly, cytotoxicity, and membrane destabilization, which were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lactate dehydrogenase (LDH)-release assays with SH-SY5Y cells, and dye leakage assays using liposomes. These findings suggest that the charge of the amino acid side chain, rather than its size or hydrophobicity, accounts for the differences in the oligomeric assembly and toxicity of the E22 familial mutants of Aβ.
AB - This work probes the role of charge in the oligomeric assembly, toxicity, and membrane destabilization of a series of peptides derived from Aβ and the E22Q and E22K familial mutants. In the mutant Aβ peptides, an acidic residue (E) is replaced with either a neutral or basic residue (Q or K), thus altering the net charge of the peptide. Acetylation at peripheral positions permits modulation of charge of the peptides and allows investigation of the role of charge in their oligomeric assembly, cytotoxicity, and membrane disruption. Peptides with the same net charge generally behave similarly even if the amino acid residue at position 22 differs. As the net charge of the peptide decreases, so does the extent of assembly, cytotoxicity, and membrane destabilization, which were determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, lactate dehydrogenase (LDH)-release assays with SH-SY5Y cells, and dye leakage assays using liposomes. These findings suggest that the charge of the amino acid side chain, rather than its size or hydrophobicity, accounts for the differences in the oligomeric assembly and toxicity of the E22 familial mutants of Aβ.
KW - Alzheimer's disease
KW - amyloid-β
KW - familial mutant
KW - net charge
KW - β-hairpin peptide
UR - http://www.scopus.com/inward/record.url?scp=85125941407&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125941407&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.1c00833
DO - 10.1021/acschemneuro.1c00833
M3 - Article
C2 - 35191689
AN - SCOPUS:85125941407
SN - 1948-7193
VL - 13
SP - 714
EP - 720
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 6
ER -