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Gallic acid disruption of Aβ1–42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse

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Title: Gallic acid disruption of Aβ1–42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse
Authors: Mei Yu, Xuwei Chen, Jihong Liu, Quan Ma, Zhan Zhuo, Hao Chen, Lin Zhou, Sen Yang, Lifeng Zheng, Chengqing Ning, Jing Xu, Tianming Gao, Sheng-Tao Hou
Source: Neurobiology of Disease, Vol 124, Iss , Pp 67-80 (2019)
Publisher Information: Elsevier, 2019.
Publication Year: 2019
Collection: LCC:Neurosciences. Biological psychiatry. Neuropsychiatry
Subject Terms: Alzheimer's disease, Gallic acid, Amyloid-β-aggregation, Morris water maze, Novel object recognition test, Y-maze, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
More Details: Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ 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 Aβ1–42 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 Aβ1–42 aggregation both in vitro and in vivo. Further, 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 ε-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 be further developed as a drug to treat AD through disrupting the formation of Aβ1–42 aggregation.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1095-953X
Relation: http://www.sciencedirect.com/science/article/pii/S0969996118302067; https://doaj.org/toc/1095-953X
DOI: 10.1016/j.nbd.2018.11.009
Access URL: https://doaj.org/article/dba616531d7643fb9bbe0034efe42106
Accession Number: edsdoj.ba616531d7643fb9bbe0034efe42106
Database: Directory of Open Access Journals
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  Data: Gallic acid disruption of Aβ1–42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse
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  Data: Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Aβ 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 Aβ1–42 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 Aβ1–42 aggregation both in vitro and in vivo. Further, 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 ε-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 be further developed as a drug to treat AD through disrupting the formation of Aβ1–42 aggregation.
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