Not Oligomers but Amyloids are Cytotoxic in the Membrane‐Mediated Amyloidogenesis of Amyloid‐β Peptides

Abstract

The formation of neurotoxic aggregates by amyloid-β peptide (Aβ) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous-phase aggregation of Aβ. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Here, aggregation processes of Aβ on living cells and cytotoxic events were monitored by fluorescence techniques. Aβ formed amyloids after forming oligomers composed of ≈10 Aβ molecules. The formation of amyloids was necessary to activate apoptotic caspase-3 and reduce the ability of the cell to proliferate; this indicated that amyloid formation is a key event in Aβ-induced cytotoxicity.

Self‐Assembly and Neurotoxicity of β‐Amyloid (21–40) Peptide Fragment: The Regulatory Role of GxxxG Motifs

“…Surprisingly, both G33 L and G37 L showed negligible toxicity, signifying that G 33 xxxG 37 motif plays a crucial role in Aβ neurotoxicity (Figure F). In contrast to the soluble monomeric state with a single conformation, aggregates have an intricate structural landscape allied with multiple aggregate‐specific activities …”

“…In contrast to the soluble monomeric state with a single conformation, aggregates have an intricate structural landscape allied with multiple aggregate-specific activities. [4] Aggregate Size and Morphology is Linked with Neurotoxicity Dynamic light scattering experiment showed a gradual increase in the hydrodynamic diameter of each peptide variants as a function of time ( Figure S6). Interestingly, as the mutation shifted towards the C-terminal, the heterogeneity in the aggregate size decreases, also found in AFM images.…”

“…Although the recent evidences on Aβ neurotoxicity have shifted the focus towards the toxic oligomers, [3] fibrils which have long been considered as the cause of disease pathogenesis and cannot be ruled out as evidences pertaining to them are still coming along. [4,5] A deeper understanding of the molecular mechanisms and pathways underlying Aβ self-aggregation remains a great challenge to current science. Over the years, independent studies have identified the central (K16-G25) and the C-terminal region (K28-G37) play a vital role in Aβ self-assembly.…”

“…Despite several decades of research on the relationship between Aβ and AD, researchers are still skeptical about the structure–toxicity correlation. Although the recent evidences on Aβ neurotoxicity have shifted the focus towards the toxic oligomers, fibrils which have long been considered as the cause of disease pathogenesis and cannot be ruled out as evidences pertaining to them are still coming along . A deeper understanding of the molecular mechanisms and pathways underlying Aβ self‐aggregation remains a great challenge to current science.…”

Computational Study on the Assembly of Amyloid β-Peptides in the Hydrophobic Environment

“…In addition to the simulation time, the number of Aβ peptides in the calculation model is needed to be increased to raise the Aβ concentration for optimal calculation condition suitable for β-sheet formation. The number of Aβ molecules in a β-sheet-rich oligomer was estimated to be about 15 for fibrillation on GM1-containing artificial membranes 30) and neuronal cells. 31) The commonly observed forms of toxic Aβ peptides consist of 40 and 42 residues, and the latter is the major constituent of senile plaque.…”