2022
DOI: 10.1021/acs.jpclett.2c02998
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Nanoscale Infrared Spectroscopy Identifies Parallel to Antiparallel β-Sheet Transformation of Aβ Fibrils

Abstract: Spontaneous aggregation of amyloid beta (Aβ) proteins leading to the formation of oligomers and eventually into fibrils has been identified as a key pathological signature of Alzheimer's disease. The structure of late-stage aggregates have been studied in depth by conventional structural biology techniques, including nuclear magnetic resonance, Xray crystallography, and infrared spectroscopy; however, the structure of early-stage aggregates is less known due to their transient nature. As a result, the structur… Show more

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Cited by 11 publications
(17 citation statements)
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“…Hence the maturation of oligomeric species into fibrils for the Aβ Dutch mutant proceeds through intermediate fibrillar aggregates that have more relative antiparallel character than mature fibrils: essentially the structural transition from antiparallel to parallel occurs in the fibril phase and not in oligomers. We have previously demonstrated that similar structural transitions can occur in smaller wild-type Aβ fragments 34 ; the findings reported here point to secondary structural reorganization in fibrils as a more ubiquitous trait of amyloid aggregation. The overall and antiparallel β-sheet populations also increase between the 2 h type 2 oligomers and the 36-72 h fibrils, which is expected if the former were to evolve into the latter.…”
Section: Resultssupporting
confidence: 76%
“…Hence the maturation of oligomeric species into fibrils for the Aβ Dutch mutant proceeds through intermediate fibrillar aggregates that have more relative antiparallel character than mature fibrils: essentially the structural transition from antiparallel to parallel occurs in the fibril phase and not in oligomers. We have previously demonstrated that similar structural transitions can occur in smaller wild-type Aβ fragments 34 ; the findings reported here point to secondary structural reorganization in fibrils as a more ubiquitous trait of amyloid aggregation. The overall and antiparallel β-sheet populations also increase between the 2 h type 2 oligomers and the 36-72 h fibrils, which is expected if the former were to evolve into the latter.…”
Section: Resultssupporting
confidence: 76%
“…Furthermore, the fibrils studied here are in early stages of maturation and can undergo additional evolution that alters the relative population of antiparallel structure. We have recently demonstrated such structural evolution in the fibrillar phase for Aβ 16-22 40 . Nonetheless, these results demonstrate deviation from the expected parallel structure in wild-type Aβ 1-42 fibrils.…”
Section: Resultsmentioning
confidence: 86%
“…The results shown here provide a validation of the generality of our previous findings. While 40 or 42 residue wild-type Aβ peptides form parallel β-sheets in-vitro, it is known that smaller fragments of Aβ spanning the amyloidogenic segment, such as Aβ 16-22 or 11-28, can form antiparallel β-sheets 39,40 . These fragments have also been isolated from AD brain tissues 41 ; hence observation of antiparallel structure can thus arise from the presence of these shorter fragments in plaques.…”
Section: Resultsmentioning
confidence: 99%
“…We therefore conclude that these fibrils are not strictly polymorphs in the morphological sense but rather represent ‘structural polymorphs’: that is, they have different secondary structure but similar morphology. We have previously identified evidence of such structural polymorphism in fibrillar aggregates of tau [ 30 ] and short Aβ derived peptide sequences [ 32 ], but never in Aβ itself. Fibrils generated after 24 h and 72 h of aggregation exhibit the same trend ( Figure 3 A–H) In both cases, we identified the presence of two distinct fibril subtypes that exhibit the above spectral differences ( Figure 3 B,D,F,H).…”
Section: Resultsmentioning
confidence: 99%