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A critical role for the self-assembly of Amyloid-?1-42 in neurodegeneration.


ABSTRACT: Amyloid ?1-42 (A?1-42) plays a central role in Alzheimer's disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of A?1-42 (vA?1-42) differing in only two amino acids. Unlike A?1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while A?1-42 oligomers impact on synaptic function, vA?1-42 does not. In a living animal model system we demonstrate that only A?1-42 leads to memory deficits. Our findings underline a key role for peptide sequence in the ability to assemble and form toxic structures. Furthermore, our non-toxic variant satisfies an unmet demand for a closely related control peptide for A?1-42 cellular studies of disease pathology, offering a new opportunity to decipher the mechanisms that accompany A?1-42-induced toxicity leading to neurodegeneration.

SUBMITTER: Marshall KE 

PROVIDER: S-EPMC4957119 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer's disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids. Unlike Aβ1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while Aβ1-42 oligomers impact on synaptic function, vAβ1-42 do  ...[more]

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