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bioRxiv · 10.1101/258848

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

Yu, M.·Chen, X.·Liu, J.·Ma, Q.·Chen, H.·Zhou, L.·Yang, S.·Zheng, L.·Ning, C.·Gao, T.·Xu, J.·Hou, S.-T.
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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.

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Yu, M., Chen, X., Liu, J., Ma, Q., Chen, H., Zhou, L., Yang, S., Zheng, L., Ning, C., Gao, T., Xu, J., Hou, S.-T.. 2018-02-02. Gallic Acid Disrupts Aβ1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse. https://doi.org/10.1101/258848

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