Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway

Wani, Abubakar; Gupta, Mehak; Ahmad, Manzoor; Shah, Aabid Manzoor; Ahsan, Aitizaz Ul; Qazi, Parvaiz Hassan; Malik, Fayaz; Singh, Gurdarshan; Sharma, Parduman R.; Kaddoumi, Amal; Bharate, Sandip B.; Vishwakarma, Ram A.; Kumar, Ajay

doi:10.1080/15548627.2019.1596476

Cited by 94 publications

(73 citation statements)

References 54 publications

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“…IFN-γ treatment normalized the levels of p-AKT and p-mTOR, which were abnormally activated both in the vitro and vivo experiments, indicating that AKT and mTOR may be the downstream kinases involved in IFN-γ signal transduction. In line with this result, a recent study reported that alborixin clears Aβ by inducing autophagy through the PTENmediated inhibition of the AKT pathway 50 .…”

Section: Discussionsupporting

confidence: 55%

Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice

Yang

Xing

et al. 2020

Cell Death Dis

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Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-β (Aβ) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aβ degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-γ significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-γ protected BV2 cells from Aβ toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-γ enhanced autophagic flux, probably through suppressing the AKT/ mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-γ and Aβ, and surrounded Aβ in APP/PS1;CX3CR1-GFP +/− mice. In addition, IFN-γ treatment decreased the Aβ plaque load in the cortex and hippocampus and rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-γ restores microglial autophagy to induce the phagocytosis of cerebral Aβ, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.

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Section: Discussionsupporting

confidence: 55%

Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice

Yang

Xing

et al. 2020

Cell Death Dis

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“…Evidence obtained by Cho et al (2014) indicates that microglial cells in culture are able to ingest and degrade extracellular Aβ fibrils after a 2-h exposure via the lysosomal system in an inflammasomemediated manner. More recently, the interplay between a u t o p h a g y m a c h i n e r y, l y s o s o m a l a c t i v i t y, inflammasome assembly, and neuroinflammation was considered a key event in AD progression (Houtman et al 2019;Wani et al 2019). In this context, it is imperative to know whether autophagy remains functional in the aged brain, where microglial cells are dystrophic due to chronic exposure to Aβ, proinflammatory cytokines, and damage-associated molecules.…”

Section: Introductionmentioning

confidence: 99%

Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

et al. 2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during AD progression. PDAPPJ20 mice-murine model of AD-exhibited an accumulation of the autophagy receptor p62 and ubiq-uitin+ aggregates in Iba1+ microglial cells close to amyloid deposits in the hippocampus. Moreover, cultured microglial BV-2 cells showed an enhanced autophagic flux during a 2-h exposure to fibrillar Aβ, which was decreased if the exposure was prolonged to 24 h, a condition analogous to the chronic exposure to Aβ in the human pathology. The autophagic impairment was also associated with lysosomal damage, depicted by membrane permeabilization as shown by the presence of the acid hydrolase cathepsin-D in cytoplasm and altered LysoTracker staining. These results are compatible with microglial exhaustion caused by proinflammatory conditions and persistent exposure to aggregated Aβ peptides. In addition, we found LC3positive autophagic vesicles accumulated in phagocytic CD68+ microglia in human AD brain samples, suggesting defective autophagy in microglia of AD brain. Our results indicate that the capacity of microglia to degrade Aβ and potentially other proteins through autophagy may be negatively affected as the disease progresses. Preserving autophagy in microglia thus emerges as a promising approach for treating AD.

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“…To identify whether D609 inhibits oxidative stress-induced cell death in RPE cells via its previously reported antioxidative mechanism in cells, 20,21 we examined the DNA oxidative damage indicators 8-hydroxy-2′-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS), which are classic oxidative stress biomarkers. 22,23 The 8-OHdGimmunostaining results showed that D609 could efficiently decrease the 8-OHdG-positive ftRPE cell number, which was increased by SI ( Fig. 3a).…”

Section: D609 Inhibited the Oxidative And Mitochondrial Damage In Ftrmentioning

confidence: 98%

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

Wang

et al. 2020

Sig Transduct Target Ther

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Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium (RPE) cell death, which is considered to be the primary cause of dry age-related macular degeneration (AMD), leading to blindness in the elderly. However, an effective therapy for this disease is lacking. Here, we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate (SI)-induced oxidative cell death and prolonged their healthy survival. D609 effectively attenuated excessive reactive oxygen species (ROS) and prevented severe mitochondrial loss due to oxidative stress in the RPE cells. Surprisingly, the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein. The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model. These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609, which may ultimately have clinical applications for the treatment of AMD.Signal Transduction and Targeted Therapy (2020) 5:20; https://doi.

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Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway

Cited by 94 publications

References 54 publications

Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice

Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice

Microglial autophagy is impaired by prolonged exposure to β-amyloid peptides: evidence from experimental models and Alzheimer’s disease patients

D609 protects retinal pigmented epithelium as a potential therapy for age-related macular degeneration

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