Deamidation of Alzheimer’s Amyloid Beta(1-42) Peptide Redirects Aggregation Pathways

Alzheimer’s disease is believed to be mainly caused by the aggregation of amyloid-β (Aβ) peptide, a fragment of the amyloid precursor protein (APP) found in the brain that affects over 55 million people worldwide. The aggregation of Aβ leads to the formation of toxic, transient intermediates known as oligomers, which subsequently aggregate to form β-sheet fibrils. Among Aβ isoforms, the 40-residue form, Aβ40, predominates, but the 42-residue form, Aβ42, is significantly more toxic. From structural studies, the salt bridge formation between Asp23 and Lys28 in Ab42 is theorized to stabilize the β-hairpin conformation, which acts as a seed that promotes the formation of oligomers and fibrils. Therefore, the Paravastu lab aims to engineer deamidation mutations that could disrupt these stabilizing interactions, such as the salt bridge, and, in turn, prevent the formation of toxic aggregates. Previous work by Foley et al. [1] demonstrated that substitution of L-Serine with D-Serine at S26 can form intramolecular H-bonds between s26 and N27 that led to altered cytotoxicity. Therefore, we examine the N27D and Q15E deamidation mutations better to understand their impact on peptide stability and aggregation pathways. We hypothesized that deamidation may reduce oligomer formation while still allowing the peptide to perform its physiological functions.

In our ongoing study, we compared the aggregation behavior of wild-type A42 to Aβ42-N27D and found that Aβ-N27D is less prone to aggregate, forming about 70% fewer oligomers than Aβ42-WT. The aggregation of the N27D mutant also has a longer lag phase than the WT. We then tested Q15E using size exclusion chromatography and observed similar behavior, with reduced oligomer formation compared to Aβ42-WT. These findings offer insight into the molecular mechanisms driving Aβ42 aggregation. Future studies will further investigate the structural changes caused by deamidation and how these alterations affect cytotoxicity profiles. They highlight deamidation as a potential pathway to modify aggregation, providing an alternative to the standard approach that focuses on complete clearance of aggregates and plaques. This could potentially lead to a therapeutic strategy for Alzheimer’s disease.

References:

[1] Foley, A. R.; Finn, T. S.; Kung, T.; Hatami, A.; Lee, H.-W.; Jia, M.; Rolandi, M.; Raskatov, J. A. Trapping and Characterization of Nontoxic Aß42 Aggregation Intermediates. ACS Chem. Neurosci. 2019, 10 (8), 3880-3887. https://doi.org/10.1021/acschemneuro.9600340