Gallic Acid Disrupts Aβ1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse
Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing drugs capable of preventing Aβ 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 Aβ1-42 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 Aβ1-42 aggregation from forming toxic oligomers and fibrils. Indeed, pre-incubating GA with oligomeric Aβ1-42 reduced Aβ1-42-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 Aβ1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and ω-amino group of Lys16 is also critical for the disruption of Aβ1-42 S-shaped triple-β-motif and toxicity. Together, these studies demonstrated that GA can prevent and protect the AD brain through disrupting Aβ1-42 aggregation.
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