The Resveratrol Trimer Miyabenol C Inhibits β-Secretase Activity and β-Amyloid Generation

Abstract

Accumulation and deposition of amyloid-β peptide (Aβ) in the brain is a primary cause of the pathogenesis of Alzheimer’s disease (AD). Aβ is generated from amyloid-β precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase. Inhibiting β-secretase activity is believed to be one of the most promising strategies for AD treatment. In the present study, we found that a resveratrol trimer, miyabenol C, isolated from stems and leaves of the small-leaf grape (Vitisthunbergii var. taiwaniana), can markedly reduce Aβ and sAPPβ levels in both cell cultures and the brain of AD model mice. Mechanistic studies revealed that miyabenol C affects neither protein levels of APP, the two major α-secretases ADAM10 and TACE, and the γ-secretase component Presenilin 1, nor γ-secretase-mediated Notch processing and TACE activity. In contrast, although miyabenol C has no effect on altering protein levels of the β-secretase BACE1, it can inhibit both in vitro and in vivo β-secretase activity. Together, our results indicate that miyabenol C is a prominent β-secretase inhibitor and lead compound for AD drug development.

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…Later, Hu et al. found that miyabenol C significantly inhibits β‐secretase and reduces the generation of Aβ both in vitro and in vivo . Miyabenol C does not show cytotoxicity at low doses (5–20 μ m ); however, dose‐dependent cytotoxicity is observed at higher doses (40–100 μ m ).…”

“…Amiodaronea nd bepridil inhibit b-secretase cleavage at therapeutically achievable concentrations in vivo in guineap igs. [78] Benzofuran-a nd indole-based inhibitors such as dehydroevodiamineh ydrochloride (DHED), [113] posiphen, [56] indomethacin, [82] DP-155, [84] KMS88009, [90] 2-methyl-5-(3-{4-[(S)methylsulfinyl]phenyl}-1-benzofuran-5-yl)-1,3,4-oxadiazolein (MMBO), [101] tadalafil, [100] melatonin, [130] and tubastatin A [126] have been proven to be effective in at ransgenic mice model of AD.Afew other benzofuran-and indole-based compounds such miyabenol C, [140] indomethacin, [82,83] 28, [88] K252a, [97] 35 bd, [105] tacrine-melatonin hybrid 38, [118,119] 39 d, [120] 64 c/64 d, [134] 68 d, [138] 75, [145] and 77 [147] have been tested in cellular models.…”

“…found that miyabenol Cs ignificantly inhibits bsecretase and reduces the generation of Ab both in vitro and in vivo. [140] Miyabenol Cd oes not show cytotoxicity at low doses (5-20 mm); however,d ose-dependentc ytotoxicity is observeda th igher doses (40-100 mm). Miyabenol Cc onsiderably lowerst he levels of Ab40 and Ab42 in N2a695 cells in ad osedependentm anner.I nN 2a695 cells, miyabenol Ct reatment results in decreased levels of sAPPb (an amino-terminal fragment of APP generatedb yb-secretase cleavage) and APP b-CTF (a carboxyl-terminal fragment of APP generated by b-secretase cleavage), signifying that miyabenol Cr educes Ab generation by inhibiting b-secretaseactivity.…”

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

“…130,131 This promising approach inspires further efforts to develop efficient BSIs. 139 c-Secretase inhibitors. The study showed p-p interaction of BSIs with a side chain of F108 of the flap pocket.…”

Evaluation of Plant Food Extracts in Experimental Model of Alzheimer's Like Disease Induced by Aluminum Lactate in Rats

“…Resveratrol, a polyphenolic compound, can cross the blood-brain barrier and exert its neuroprotective effect as a radical scavenger through increasing heme oxygenase 1 activity which used to degrade the pro-oxidant heme (iron-protoporphyrin IX). Resveratrol has protective role in AD through inhibiting betasecretase and beta-amyloid generation (Hu et al, 2015).The polyphenols in grape skin was reported to have protective role in degenerative and inflammatory diseases as well as enhancing brain mitochondrial respiration leading to improvement of dementia in aged mice (Calabriso et al, 2016;Asseburg et al, 2016).…”