The Amyloid Aggregation Accelerator Diacetyl Prevents Cognitive Decline in Alzheimer's Mouse Models.

Diacetyl (DA), a food flavorant, is linked with occupational lung disease. Our experiments described the formation of a covalent adduct by DA with Arg of the Aβ peptide, which resulted in only a transient increase in neurotoxicity in SH-SY5Y cells. However, 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 Aβ plaque burden and decreased neuronal inflammation in the transgenic AD mice. Additionally, cognitive impairment induced by intracerebroventricular Aβ 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 Aβ aggregation by DA into nontoxic plaques. The data from SDS-PAGE, dot-blot, and TEM experiments corroborated the acceleration of the Aβ aggregation observed in AD animal models and characterized the DA-induced formation of Aβ fibrils. Such Aβ-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 Aβ. Taken together, the results of this study present for the first time the implications of the DA-induced acceleration of Aβ and may provide a strategy for the rational design of Aβ aggregation accelerators as AD therapeutics that promote oligomer-free Aβ fibril formation.