A Structure-Toxicity Study of Aß42 Reveals a New Anti-Parallel Aggregation Pathway

Abstract

Amyloid beta (Aβ) peptides produced by APP cleavage are central to the pathology of Alzheimer’s disease. Despite widespread interest in this issue, the relationship between the auto-assembly and toxicity of these peptides remains controversial. One intriguing feature stems from their capacity to form anti-parallel ß-sheet oligomeric intermediates that can be converted into a parallel topology to allow the formation of protofibrillar and fibrillar Aβ. Here, we present a novel approach to determining the molecular aspects of Aß assembly that is responsible for its in vivo toxicity. We selected Aß mutants with varying intracellular toxicities. In vitro, only toxic Aß (including wild-type Aß42) formed urea-resistant oligomers. These oligomers were able to assemble into fibrils that are rich in anti-parallel ß-sheet structures. Our results support the existence of a new pathway that depends on the folding capacity of Aß .

Theory of concentric β-barrel structures: models of amyloid beta 42 oligomers, annular protofibrils, and transmembrane channels

“…More important, recent experiments indicate that some Aβ42 oligomers do have an antiparallel β secondary structure that is similar to that of OMPA 13 (an antiparallel β-barrel channel), and antibodies that recognize Aβ42 oligomers also recognize some toxins that form antiparallel β-barrel transmembrane channels 15,16 . Also, antiparallel oligomers are more toxic than those with parallel structures 13,14 . (3) Concentric βbarrels had never been observed when we proposed the structures.…”

“…Effects of the Osaka mutation (E22Δ) may be due to a similar effect since it would move the negatively charged D23 side chain from the hydrophobic side of S2 to the polar side, and move the hydrophobic V24 side chain from the polar side to the more hydrophobic side. Aβ42 mutations that increase the toxicity in a yeast screening system also increase formation of antiparallel assemblies 14 . However, effects of most Aβ mutations that affect AD on formation and properties of Aβ oligomers, APFs and ion channels have not been studied.…”

“…The single channel conductance of all of these channels is greater than that reported by Serra-Batiste et al 10 . The membrane channel hypothesis for AD thus provides an explanation why antiparallel Aβ42 oligomers are more toxic and detrimental than other forms of Aβ 13,14 . Findings that some Aβ42 oligomers have an antiparallel β secondary structure that is similar to that of OMPA (an antiparallel β-barrel channel) 13 , that antibodies to Aβ42 oligomers also recognize some toxins that form antiparallel β-barrel transmembrane channels 15,16 , and that the Iowa mutant that leads to early onset AD also causes some fibrils to adopt an antiparallel β structure 6 support our hypothesis 17,18 that Aβ42 oligomers, annular protofibrils, and channels possess concentric antiparallel β-barrels.…”

Tip‐Enhanced Raman Spectroscopy to Distinguish Toxic Oligomers from Aβ1–42 Fibrils at the Nanometer Scale

“…Ford ecades,i solating and characterizing the oligomer species has constituted the key process for diagnosing, preventing,and treating the associated diseases.Previous studies in ATR-FTIR spectroscopy revealed that the secondary structure of the oligomers organized in anti-parallel bsheets seems to be af ingerprint of the toxic species,i n contrast with parallel b-sheets observed for the long fibers. [9,10] However,those FTIR spectra were recorded for crystals after sample drying and the method averaged the spectral signatures associated with all the species present in the samples, including monomers,o ligomers,f ibrils,a nd fibers.T ERS is recommended to establish the fingerprint of fibers and oligomers at the nanometer scale.…”

“…Am arked morphological change is therefore observed for these three peptide aggregates,w hich are known to have different cytotoxicity. [10] However,topographical AFM imaging cannot be used to distinguish them when amyloid plaques form on cell membranes,and amore specific characterization is thus required.…”