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The effect of Osaka mutation on oligomer formation of full-length amyloid [beta]-protein oligomers
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The effect of Osaka mutation on oligomer formation of full-length amyloid [beta]-protein oligomers

Riya Shah
Master of Science (M.S.), Drexel University
Jun 2022
DOI:
https://doi.org/10.17918/00001158
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Abstract

Alzheimer's disease Amyloid beta-protein Oligomers
Alzheimer's disease (AD) is the leading cause of dementia among the elderly and is characterized by loss of memory due to neuronal death. In vitro and in vivo experiments have identified soluble, low-molecular weight, non-covalently bonded oligomeric forms of amyloid [beta]-protein (A) as the likely toxic species that leads to AD. The Osaka mutation ([E22[delta]]), discovered in a Japanese family, is associated with an early-onset AD in the carriers of this mutation, and involves a deletion of the glutamic acid at the twenty-second position in A[beta]. A[beta] with Osaka mutation can be used to probe the effect of singular deletions on oligomerization and protein conformations. We use discrete molecular dynamics (DMD) simulations with a four-bead protein model and implicit solvent to study the oligomerization of the two most predominant alloforms, A[beta]1-40 and A[beta]1-42, and their Osaka mutants. Our findings suggest that the Osaka mutation alters A[beta]1-40 structure and assembly mechanics to be more similar to A[beta]1-42 and [E22[delta]]A[beta]1-42. Specifically, the Osaka mutation greatly affects the secondary structure of A[beta]1-40 in the N-terminal region to make it resemble A[beta]1-42. We also show that [E22[delta]]A[beta]1-40 and [E22[delta]]A[beta]1-42 tend to assemble into larger oligomers than their wild-type (WT) counterparts and that both mutants are more prone than wild type A[beta] to forming a tertiary contact between D23 and K28. The proximity of negatively charged D23 and positively charged K28 is expected to induce an intrapeptide salt bridge, stabilization of which is known for speeding up fibril formation. These results provide a plausible explanation of why Osaka mutants aggregate into fibrils much faster than WT peptides. The early-onset properties of the Osaka mutation might be attributed to the resemblance of [E22[delta]]A[beta]1-40 oligomer conformations to those formed by A[beta]1-42, specifically the property of A[beta]1-42 possessing disordered and solvent accessible N-termini, which would readily interact with and potentially disrupt cellular membranes.

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