Abstract
Alzheimer's disease (AD) is a devastating brain disorder characterized by neurofibrillary tangles and amyloid plaques. Inhibiting Tau protein and amyloid-beta (Aβ) production or removing these molecules is considered potential therapeutic strategies for AD. Genipin is an aglycone and is isolated from the extract of Gardenia jasminoides Ellis fruit. In this study, the effect and molecular mechanisms of genipin on the inhibition of Tau aggregation and Aβ generation were investigated. The results showed that genipin bound to Tau and protected against heparin-induced Tau fibril formation. Moreover, genipin suppressed Tau phosphorylation probably by downregulating the expression of CDK5 and GSK-3β, and activated mTOR-dependent autophagy via the SIRT1/LKB1/AMPK signaling pathway in Tau-overexpressing cells. In addition, genipin decreased Aβ production by inhibiting BACE1 expression through the PERK/eIF2α signaling pathway in N2a/SweAPP cells. These data indicated that genipin could effectively lead to a significant reduction of phosphorylated Tau level and Aβ generation in vitro, suggesting that genipin might be developed into an effective therapeutic complement or a potential nutraceutical for preventing AD.
Highlights
Alzheimer’s disease (AD) is a devastating and irreversible progressive brain illness and is the most common type of dementia diagnosed in elderly individuals
The following antibodies were used in this study: anti-Tau, anti-phospho-T231, antiphospho-S396, anti-phospho-S404, anti-cyclindependent kinase 5 (CDK5), anti-phospho-Glycogen synthase kinase-3β (GSK-3β) (Tyr216), anti-LC3, anti-amyloid precursor protein (APP), anti-Aβ, anti-β-secretase 1 (BACE1), and anti-β-actin (Abcam, Cambridge, UK); anti-p62, antiBeclin-1, anti-silent information regulator of transcription 1 (SIRT1), anti-liver kinase B1 (LKB1), anti-phospho-LKB1, anti-Adenosine monophosphate-activated protein kinase (AMPK), anti-phospho-AMPK, anti-mechanistic target of rapamycin (mTOR), antiphospho-mTOR, anti-p70 ribosomal protein S6 kinase (p70S6K), anti-phospho-p70S6K, anti-protein kinase RNA-like endoplasmic reticulum kinase (PERK), anti-phospho-PERK, anti-eukaryotic translation initiation factor-2a (eIF2a), and antiphospho-eIF2a (Cell Signaling Technology, Beverly, MA, USA)
These results demonstrated that genipin effectively inhibited Tau-R3 aggregation in Thioflavin T (ThT) fluorescence and Transmission electron microscopy (TEM) assays
Summary
Alzheimer’s disease (AD) is a devastating and irreversible progressive brain illness and is the most common type of dementia diagnosed in elderly individuals. Methylene blue has been reported to reduce tau pathology and neuron death in the Tau transgenic mouse model, while the second-generation derivative of methylene blue (LMTM) was not effective in two different phase 3 trials[6, 7]. Tideglusib, a GSK-3 inhibitor, could reduce both Tau phosphorylation and amyloid deposition in transgenic mice[8], but a phase 2 trial showed no effect of this drug on decreasing the speed of cognitive or functional decline[9]. Despite the very large effort put in AD medication development, there is currently no disease-modifying treatment[4]. It is more important than ever to identify novel and effective therapeutics for AD
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