TY - JOUR
T1 - Probing differences among Aβ oligomers with two triangular trimers derived from Aβ
AU - Kreutzer, Adam G.
AU - Guaglianone, Gretchen
AU - Yoo, Stan
AU - Parrocha, Chelsea Marie T.
AU - Ruttenberg, Sarah M.
AU - Malonis, Ryan J.
AU - Tong, Karen
AU - Lin, Yu Fu
AU - Nguyen, Jennifer T.
AU - Howitz, William J.
AU - Diab, Michelle N.
AU - Hamza, Imane L.
AU - Lai, Jonathan R.
AU - Wysocki, Vicki H.
AU - Nowick, James S.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/5/30
Y1 - 2023/5/30
N2 - The assembly of the β-amyloid peptide (Aβ) to form oligomers and fibrils is closely associated with the pathogenesis and progression of Alzheimer’s disease. Aβ is a shape-shifting peptide capable of adopting many conformations and folds within the multitude of oligomers and fibrils the peptide forms. These properties have precluded detailed structural elucidation and biological characterization of homogeneous, well-defined Aβ oligomers. In this paper, we compare the structural, biophysical, and biological characteristics of two different covalently stabilized isomorphic trimers derived from the central and C-terminal regions Aβ. X-ray crystallography reveals the structures of the trimers and shows that each trimer forms a ball-shaped dodecamer. Solution-phase and cell-based studies demonstrate that the two trimers exhibit markedly different assembly and biological properties. One trimer forms small soluble oligomers that enter cells through endocytosis and activate capase-3/7-mediated apoptosis, while the other trimer forms large insoluble aggregates that accumulate on the outer plasma membrane and elicit cellular toxicity through an apoptosis-independent mechanism. The two trimers also exhibit different effects on the aggregation, toxicity, and cellular interaction of full-length Aβ, with one trimer showing a greater propensity to interact with Aβ than the other. The studies described in this paper indicate that the two trimers share structural, biophysical, and biological characteristics with oligomers of full-length Aβ. The varying structural, assembly, and biological characteristics of the two trimers provide a working model for how different Aβ trimers can assemble and lead to different biological effects, which may help shed light on the differences among Aβ oligomers.
AB - The assembly of the β-amyloid peptide (Aβ) to form oligomers and fibrils is closely associated with the pathogenesis and progression of Alzheimer’s disease. Aβ is a shape-shifting peptide capable of adopting many conformations and folds within the multitude of oligomers and fibrils the peptide forms. These properties have precluded detailed structural elucidation and biological characterization of homogeneous, well-defined Aβ oligomers. In this paper, we compare the structural, biophysical, and biological characteristics of two different covalently stabilized isomorphic trimers derived from the central and C-terminal regions Aβ. X-ray crystallography reveals the structures of the trimers and shows that each trimer forms a ball-shaped dodecamer. Solution-phase and cell-based studies demonstrate that the two trimers exhibit markedly different assembly and biological properties. One trimer forms small soluble oligomers that enter cells through endocytosis and activate capase-3/7-mediated apoptosis, while the other trimer forms large insoluble aggregates that accumulate on the outer plasma membrane and elicit cellular toxicity through an apoptosis-independent mechanism. The two trimers also exhibit different effects on the aggregation, toxicity, and cellular interaction of full-length Aβ, with one trimer showing a greater propensity to interact with Aβ than the other. The studies described in this paper indicate that the two trimers share structural, biophysical, and biological characteristics with oligomers of full-length Aβ. The varying structural, assembly, and biological characteristics of the two trimers provide a working model for how different Aβ trimers can assemble and lead to different biological effects, which may help shed light on the differences among Aβ oligomers.
KW - Alzheimer’s disease
KW - Aβ oligomers
KW - X-ray crystallography
KW - cellular toxicity
KW - native mass spectrometry
UR - http://www.scopus.com/inward/record.url?scp=85159817031&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85159817031&partnerID=8YFLogxK
U2 - 10.1073/pnas.2219216120
DO - 10.1073/pnas.2219216120
M3 - Article
C2 - 37216514
AN - SCOPUS:85159817031
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
M1 - e2219216120
ER -