Diacetyl (DA), a food flavorant, is linked with occupational lung disease. Our in vitro experiments described the formation of a covalent adduct by DA with Arg5 of the Aβ1-42 peptide, which resulted in only a transient increase in neurotoxicity in SH-SY5Y cells. However, in vivo implications of these effects on Alzheimer's disease (AD) pathogenesis and the underlying mechanisms remain poorly understood. In the APP/PS1 transgenic AD mouse model, DA treatment did not exacerbate learning and memory deficits in the Morris water maze test. Moreover, DA increased the Aβ1-42 plaque burden and decreased neuronal inflammation in the transgenic AD mice. Additionally, cognitive impairment induced by intracerebroventricular Aβ1-42 was restored by the DA treatment, as assessed by the T-maze test. A corresponding mitigation of neuronal inflammation was also observed in the hippocampus of these nontransgenic mice due to the acceleration of Aβ1-42 aggregation by DA into nontoxic plaques. The data from SDS-PAGE, dot-blot, and TEM in vitro experiments corroborated the acceleration of the Aβ1-42 aggregation observed in vivo in AD animal models and characterized the DA-induced formation of Aβ1-42 fibrils. Such Aβ1-42-DA fibrils were unstable in the presence of detergent and amenable to detection by the thioflavin T reagent, thus underscoring the distinct assembly of these fibrils compared to that of the fibrils of the native Aβ1-42. Taken together, the results of this study present for the first time the in vivo implications of the DA-induced acceleration of Aβ1-42 and may provide a strategy for the rational design of Aβ1-42 aggregation accelerators as AD therapeutics that promote oligomer-free Aβ1-42 fibril formation.
Bibliographical noteFunding Information:
This work was supported by the research endowment funds from the Center for Drug Design (CDD); the Grant-in-Aid of Research, Artistry, and Scholarship program (GIA, Project 143977) at the University of Minnesota, Minneapolis; and the NIH Grant R01AG062469.
© 2021 American Chemical Society.