Gallic Acid Disrupts Aβ1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse

Abstract

Alzheimers disease (AD) treatment represents one of the largest unmet medical needs. Developing drugs capable of preventing A{beta} aggregation is an excellent 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 early stage AD mice (4-month-old), but also significantly reduced the more severe deficits in spatial learning, reference memory, short-term recognition and spatial working memory of the late stage AD mice (9-month-old). The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated late stage APP/PS1 AD mice. Atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA can reduce A{beta}1-42 aggregation from forming toxic oligomers and fibrils. Indeed, 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 {varepsilon}-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 prevent and protect the AD brain through disrupting A{beta}1-42 aggregation.