Amelia Pilar Rauter
University of Lisbon, Portugal
Title: Exploiting polyphenols for Alzheimer’s disease prevention: From nature to the lab
Biography
Biography: Amelia Pilar Rauter
Abstract
Alzheimer’s disease (AD) is a multifactorial pathology, with unknown etiology and, up to now, without cure. Solutions for early diagnosis and disease prevention are urgently needed. We present two case studies on the medicinal plants Salvia sclareoides and Genista tenera, the first one known for its effects on memory loss and the other one used to control diabetes, whose patients are at higher risk of developing AD than normal elderly. Methodologies are based on functional ingredient isolation and structure elucidation and synthesis, followed by the study of the mechanisms of action. The biological properties of S. sclareoides demonstrated that extracts are potent inhibitors of acetylcholinesterase (AChE), the enzyme degrading the neurotransmitter acetylcholine, whose inhibition is used to treat AD patients in early disease stages. Rosmarinic acid was identified as plant major component and a new binding site of AChE for this constituent was discovered [1], opening the way to new strategies for lead development. It was demonstrated that plant extracts prevent normal Prion protein to convert to Prion infectious isoform [2], and interact with AD toxic oligomers [3], removing amyloid fibrils to form amorphous aggregates. These findings clearly reinforce the potential of the plant to act on both amyloid and cholinergic events for AD prevention. Also diabetes is an amyloid disease and the scientific background of the traditional use of G. tenera has been unraveled. The active principles were mainly O- and C-glycosyl polyphenols, namely the potent antihyperglycemic 8-glucosylgenistein [4]. This discovery has encouraged the generation of a library of compounds structurally based on its precursors and analogues, and some of them demonstrated a potent antidiabetic activity [5]. The multiple mechanisms of action of the polyphenols studied were identified. α-Glucosidase and glucose 6-phosphatase inhibitory activity was shown by the polyphenols that also demonstrated UV cellular damaging protection and antioxidant activity, maintained after in vitro digestion with artificial gastric and pancreatic juices [6]. Dihydrochalcones demonstrated a selective and potent inhibition of sodium glucose co-transporter 2 [5]. Interestingly, suppression of islet amyloid polypeptide (IAPP) fibril formation was produced by 8-glucosylgenistein. Molecular recognition studies with IAPP and Aβ1-42 confirmed the same binding mode for both amyloid peptides, supporting this molecular entity for intervention in amyloid events of both diabetes and the frequently associated Alzheimer’s disease [4]. C-glucosylation has also proven to efficiently increase the antidiabetic activity of the polyphenols studied and to prevent their behavior as PAINS (Pan-Assay Interference compounds).
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References
1. Marcelo F, Dias C, Martins A, Madeira PJ, Jorge J, Florêncio MH, Cañada FJ, Cabrita EJ, Jiménez-Barbero J, Rauter AP (2013) Molecular Recognition of Rosmarinic Acid from Salvia sclareoides Extracts by Acetylcholinesterase. A New Binding Site Detected by NMR. Chemistry A European Journal 19: 6641-6649.
2. Rauter AP, Dias C, Martins A, Branco I, Neng NR, Nogueira JM, Goulart M, Silva FVM, Justino J, Trevitt C, Waltho JP (2012) Non-toxic Salvia sclareoides Brot. extracts as a source of functional food ingredients: phenolic profile, antioxidant activity and prion binding properties. Food Chemistry 132: 1930-1935.
3. Airoldi C, Sironi E, Dias C, Marcelo F, Martins A, Rauter AP, Nicotra F, Jimenez-Barbero J (2013) Natural compounds against Alzheimer’s Disease: Molecular recognition of Salvia sclareoides extract and its major component, rosmarinic acid, with Aß1-42 peptide, as investigated by NMR. Chemistry Asian Journal 8: 596-602. A. P. Rauter, et al, Food Chemistry 2012, 132(4), 1930
4. Jesus R, Dias, C., Matos AM, Almeida RFM, Viana AS, Marcelo F, Ribeiro RT, Macedo MP, Airoldi C, Nicotra F, Martins A, Cabrita EJ, Jimenéz-Barbero J, Rauter AP (2014) Exploiting the Therapeutic Potential of 8-ß-D-Glucopyranosylgenistein: Synthesis, Antidiabetic Activity and Molecular Interaction with IAPP and Aß1-42. Journal of Medicinal Chemistry 57: 9463-9472.