p62 works as a hub modulation in the ageing process

Fan, Xiaolan; Huang, Tiantian; Tong, Yingdong; Fan, Ziqiang; Yang, Ziyue; Yang, Deying; Mao, Xueping; Yang, Mingyao

doi:10.1016/j.arr.2021.101538

Cited by 16 publications

(10 citation statements)

References 148 publications

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“…Compared with the mice in the AP + SED group, aerobic exercise significantly increased the LC3-II/I ratios in the brain cells of the mice in the AP + EX group ( p < 0.01). P62 localizes autophagic substrates to autophagosomes by interacting with LC3 and is degraded by autophagy together with autophagic substrates, so it can be used as an indicator of autophagic degradation [ 27 , 29 ]. Decreased levels of P62 are associated with autophagy activation [ 27 , 29 ].…”

Section: Resultsmentioning

confidence: 99%

“…P62 localizes autophagic substrates to autophagosomes by interacting with LC3 and is degraded by autophagy together with autophagic substrates, so it can be used as an indicator of autophagic degradation [ 27 , 29 ]. Decreased levels of P62 are associated with autophagy activation [ 27 , 29 ]. As shown in Figure 5 E, compared with the mice in the WT + SED group, the level of the P62 protein in the brain cells of the mice in the AP + SED group was significantly increased ( p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

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Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Jian

Yuan

Yang

et al. 2022

IJMS

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Abnormalities in autophagy are associated with Alzheimer’s disease (AD)-like lesions. Studies have shown that exercise can significantly improve AD autophagy abnormalities, but the mechanism underlying this phenomenon remains unclear. APN not only has an important regulatory effect on AD autophagy abnormalities, but also is affected by exercise. Therefore, this study aims to reveal the pathway by which exercise regulates abnormal autophagy in AD using the APN–AdipoR1 signaling pathway as an entry point. The results of the study showed that APP/PS1 double transgenic AD model mice (24 weeks) showed decreased AdipoR1 levels in the brain, abnormal autophagy, increased Aβ deposition, and increased cell apoptosis, and dendritic spines and cognitive function were reduced. Twelve weeks of aerobic exercise enhanced lysosomes and alleviated abnormal autophagy by activating the AdipoR1/AMPK/TFEB signaling pathway in the brains of AD mice, thereby alleviating Aβ deposition and its associated AD-like abnormalities. These findings suggest that the AdipoR1 plays an important role in aerobic exercise’s alleviation of abnormal autophagy in AD brain cells and alleviation of AD-like lesions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Jian

Yuan

Yang

et al. 2022

IJMS

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“…However, SQSTM1/P62 was enhanced in HFD mice. Autophagy deficiency causes the accumulation of P62 [ 25 ], which is an autophagy substrate and has been widely used as a predictor of autophagy flux [ 26 ]. Under certain stress conditions, the increase in autophagosome synthesis may be related to a decrease in lysosome activity.…”

Section: Resultsmentioning

confidence: 99%

Dietary High-Fat Promotes Cognitive Impairment by Suppressing Mitophagy

Wen

Wang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Dietary habits contribute to the characteristics of Alzheimer’s disease (AD) and cognitive impairment, which are partly induced by the accumulation of hyperphosphorylated Tau, a microtubule-associated protein. In mice, a fat-rich diet facilitates cognitive dysfunction. However, the mechanism by which dietary fat damages the brain remains unclear. In this study, 13-month-old C57BL/6 mice were fed a normal or high-fat diet (HFD) for 6 months. Neuro-2a cells were incubated with the normal medium or palmitic acid (200 μM). Spatial memory was assessed utilizing a behavioral test. Further, western blotting and immunofluorescence techniques were used to determine the levels of mitophagy-related proteins. The synaptic morphology and phosphorylation of Tau proteins were also evaluated. Administration of HFD decreased the expression of synaptophysin and brain-derived neurotrophic factor expression, leading to significant damage to neurons. Tau protein hyperphosphorylation was detected at different loci both in vivo and in vitro. Significantly impaired learning and memory abilities, accompanied by impaired mitophagy-related processes, were observed in mice fed with HFD as compared to mice fed with normal food. In conclusion, high fatty-acid intake hinders mitophagy and upregulates Tau protein phosphorylation, including age-related synaptic dysfunction, which leads to cognitive decline.

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“…However, H 2 O 2 stimulation in the presence of phloroglucinol failed to induce an increase in LC3-II/LC3-I value or Beclin-1 expression, which could serve as markers of autophagy because they were involved in the formation of autophagosomes [ 7 , 60 ]. On the other hand, p62, an indicator of autophagic flux due to degradation in autolysosomes [ 61 , 62 ], was maintained at the control level. Therefore, phloroglucinol might protect ARPE-19 cells from H 2 O 2 -induced cellular damage, a pro-apoptotic mechanism, by counteracting the process of autophagy.…”

Section: Discussionmentioning

confidence: 99%

Phloroglucinol Attenuates DNA Damage and Apoptosis Induced by Oxidative Stress in Human Retinal Pigment Epithelium ARPE-19 Cells by Blocking the Production of Mitochondrial ROS

et al. 2022

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Phloroglucinol, a phenolic compound, is known to possess a potent antioxidant ability. However, its role in retinal cells susceptible to oxidative stress has not been well elucidated yet. Thus, the objective of this study was to evaluate whether phloroglucinol could protect against oxidative damage in cultured human retinal pigment epithelium ARPE-19 cells. For this purpose, ARPE-19 cells were stimula ted with hydrogen peroxide (H2O2) to mimic oxidative stress. Cell viability, cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, mitochondrial function, DNA damage, and autophagy were then assessed. Our results revealed that phloroglucinol ameliorated cell viability, cytotoxicity, and DNA damage in H2O2-exposued ARPE-19 cells and blocked production of ROS. Phloroglucinol also counteracted H2O2-induced apoptosis by reducing Bax/Bcl-2 ratio, blocking activation of caspase-3, and inhibiting degradation of poly (ADP-ribose) polymerase. H2O2 caused mitochondrial impairment and increased expression levels of mitophagy markers such as PINK1and PARKIN known to be associated with mitochondrial ROS (mtROS) generation and cytosolic release of cytochrome c. However, these changes were significantly attenuated by phloroglucinol. Mito-TEMPO, a selective mitochondrial antioxidant, further enhanced the protective effect of phloroglucinol against dysfunctional mitochondria. Furthermore, H2O2 induced autophagy, but not when ARPE-19 cells were pretreated with phloroglucinol, meaning that autophagy by H2O2 contributed to the pro-survival mechanism and that phloroglucinol protected ARPE-19 cells from apoptosis by blocking autophagy. Taken together, these results suggest that phloroglucinol can inhibit oxidative stress-induced ARPE-19 cell damage and dysfunction by protecting DNA damage, autophagy, and subsequent apoptosis through mitigation of mtROS generation. Thus, phloroglucinol might have therapeutic potential to prevent oxidative stress-mediated damage in RPE cells.

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p62 works as a hub modulation in the ageing process

Cited by 16 publications

References 148 publications

Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Aerobic Exercise Alleviates Abnormal Autophagy in Brain Cells of APP/PS1 Mice by Upregulating AdipoR1 Levels

Dietary High-Fat Promotes Cognitive Impairment by Suppressing Mitophagy

Phloroglucinol Attenuates DNA Damage and Apoptosis Induced by Oxidative Stress in Human Retinal Pigment Epithelium ARPE-19 Cells by Blocking the Production of Mitochondrial ROS

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