Gallic acid disruption of A beta(1-42) aggregation rescues cognitive decline of APP/PS1 double transgenic mouse

Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting A beta aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of A beta(1-42) aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of 4-month-old APP/PS1 mice, but also significantly reduced the more severe deficits developed in the 9-month-old APP/PS1 mice in terms of spatial learning, reference memory, short-term recognition and spatial working memory. The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated 9-month-old APP/PS1 mice with increased expression of synaptic marker proteins. Evidence from atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA significantly reduces A beta(1-42) aggregation both in vitro and in vivo. Further, pre-incubating GA with oligomeric A beta(1-42) reduced A beta(1-42)-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of A beta(1-42). The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and epsilon-amino group of Lys16 is also critical for the disruption of A beta(1-42) S-shaped triple-beta-motif and toxicity. Together, these studies demonstrated that GA can be further developed as a drug to treat AD through disrupting the formation of A beta(1-42) aggregation.