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Rosmarinic acid, a catechol‐containing natural product, potently inhibits amylin amyloidosis
Author(s) -
Velander Paul William,
Wu Ling,
Ray Keith,
Zhang Shijun,
Helm Richard,
Bevan David,
Xu Bin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.914.5
Subject(s) - amylin , chemistry , amyloid (mycology) , biochemistry , rosmarinic acid , population , peptide , pharmacology , medicine , endocrinology , biology , diabetes mellitus , islet , antioxidant , inorganic chemistry , environmental health
Epidemiological studies show significant association between obesity related type 2 diabetes (T2D) and risk for cerebrovascular disease and dementia (including Alzheimer's disease, AD). Amylin is a peptide hormone whose high propensity to form amyloid in the pancreas contributes to TD2 pathology. Recently, heterologous amyloid composed of amylin and amyloid beta (the causative agent and amyloid forming species in AD) has also been found in the brain tissue of individuals with AD and T2D but not age matched healthy controls. Collectively these data suggest that amylin aggregation may represent a molecular link between AD and TD2. From a targeted screening of a collection of natural compounds used in complementary medicine, we identified that rosmarinic acid (RA) is a highly potent inhibitor against amylin amyloid formation (apparent IC 50 estimated at 200 nM). Further characterization indicates that RA and its metabolites caffeic acid (CA) and salvianic acid A (SAA), exert additive anti‐amylin aggregation and cell rescue effects against amylin‐induced neurotoxicity. Using a less hydrolyzable RA analogue (RA LH ), we show that these additive effects are similar between an intact RA molecule and equimolar amounts of its hydrolyzed metabolites CA and SAA. These observations are congruent with other data that suggests the catechol moieties present in RA, RA LH , CA and SAA may play an essential role in their observed anti‐amylin aggregation activity. Our data also suggests that strong non‐covalent interactions and or site‐specific binding between RA and the amine groups in amylin, may prevent amyloid aggregation and stabilize a population of “off‐pathway” non‐toxic oligomers. The later has recently been shown with previously characterized anti‐amyloid inhibitor epigallocatechin gallate (EGCG) which is currently in clinical trials as an anti amyloid agent for AD. Support or Funding Information This work is in part supported by Virginia Tech new faculty start‐up funds, the National Institute of Food and Agriculture of USDA, Commonwealth Health Research Board, Alzheimer's and Related Diseases Research Award Fund from Virginia Center on Aging, Diabetes Action Research and Education Foundation, and Virginia Tech Center for Drug Discovery.A working model for RA mediated anti‐amylin amyloid formation and cell rescue activity against amylin‐induced cytotoxicity.