The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits

Yu, Yang; Feng, Linjing; Li, Junnan; Lan, Xiaoxin; Lixiang, A; Lv, Xiaoyan; Zhang, Ming; Chen, Li

doi:10.1016/j.bbr.2017.07.003

Cited by 61 publications

(28 citation statements)

References 27 publications

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“…Consistently, PLs essentially contribute to autophagosome formation and fusion [21]. These results are of pivotal significance since autophagy has been suggested as a protective mechanism in neurons undergoing physiological aging [38].…”

Section: Discussionmentioning

confidence: 60%

The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

Daniele

Mangano

Durando

et al. 2020

IJMS

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Brain aging involves changes in the lipid membrane composition that lead to a decrease in membrane excitability and neurotransmitter release. These membrane modifications have been identified as contributing factors in age-related memory decline. In this sense, precursors of phospholipids (PLs) can restore the physiological composition of cellular membranes and produce valuable therapeutic effects in brain aging. Among promising drugs, alpha-glycerylphosphorylethanolamine (GPE) has demonstrated protective effects in amyloid-injured astrocytes and in an aging model of human neural stem cells. However, the compound properties on mature neuronal cells remain unexplored. Herein, GPE was tested in human hippocampal neurons, which are involved in learning and memory, and characterized by a functional cholinergic transmission, thus representing a valuable cellular model to explore the beneficial properties of GPE. GPE induced the release of the main membrane phospholipids and of the acetylcholine neurotransmitter. Moreover, the compound reduced lipid peroxidation and enhanced membrane fluidity of human brain cells. GPE counteracted the DNA damage and viability decrease observed in in vitro aged neurons. Among GPE treatment effects, the autophagy was found positively upregulated. Overall, these results confirm the beneficial effects of GPE treatment and suggest the compound as a promising drug to preserve hippocampal neurons and virtually memory performances.

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Section: Discussionmentioning

confidence: 60%

The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

Daniele

Mangano

Durando

et al. 2020

IJMS

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“…In addition, all of changes were less severe in TLR4 KO mice. A correlation has been shown between aging-related cognitive decline in healthy older adults and elevated plasma levels of IL-6 and Bax/Bcl ratio [31,32]. Moreover, IL-1β, TNF-α production and an increase in the apoptosis can reduce adult hippocampal neurogenesis and produce the age-related cognitive decline [33,34].…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice

et al. 2020

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Toll-like receptor 4 (TLR4) is a crucial receptor in neuroinflammation and apoptotic neuronal death, and increasing evidences indicated that β2-microglobulin (B2M) is thought to be a major contributor to age-related cognitive decline. In present study, we designed to investigate the effects of TLR4 on B2M-induced age-related cognitive decline. Wild-type (WT) C57BL/6, TLR4 knockout (TLR4-KO) mice and hippocampal neurons from the two type mice were respectively divided into two groups: (1) Veh group; (2) B2M-treated group. The behavioral responses of mice were measured using Morris Water Maze. Hippocampal neurogenesis and neuronal damage, inflammatory response, apoptosis, synaptic proteins and neurotrophic factors, and TLR4/MyD88/NF-κB signaling pathway proteins were examined using molecular biological or histopathological methods. The results showed that WT mice received B2M in the DG exhibited age-related cognitive declines, increased TLR4 mRNA expression and high levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and apoptotic neuronal death in the hippocampus, which were partially attenuated in TLR4-KO mice. Moreover, in absence of TLR4, B2M treatment improved hippocampus neurogenesis and increased synaptic related proteins. Our cell experiments further demonstrated that deletion of TLR4 could significantly increase synaptic related protein, decrease neuroinflammatory fators, inhibited apoptotic neuronal death, and regulated MyD88/NF-κB signal pathway after B2M treatment. In summary, our results support the TLR4 contributes to B2M-induced age-related cognitive decline due to neuroinflammation and apoptosis through TLR4/MyD88/NF-κB signaling pathway via a modulation of hippocampal neurogenesis and synaptic function. This may provide an important neuroprotective mechanism for improving age-related cognitive decline.

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“…A number of reports have indicated that abnormal autophagy promotes the activation of apoptotic cascades, ultimately leading to neuronal death, which can be alleviated by autophagy inhibitors, such as 3-methyladenine (3-MA) and DL-3-n-butylphthalide (Sun et al, 2018;Yu et al, 2018;Zhang, Wang, Li, Huang, & Sun, 2014). Therefore, autophagy in neurons appears to be delicately modulated and whether it is beneficial or harmful in neurological diseases depends on the balance between the amount of substrate and the capacity of the autophagy machinery (Yu et al, 2017). Therefore, autophagy in neurons appears to be delicately modulated and whether it is beneficial or harmful in neurological diseases depends on the balance between the amount of substrate and the capacity of the autophagy machinery (Yu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…However, contradictory results also demonstrated that autophagy is likely to play a protective role in neuronal injury, and activation of autophagy inhibits neuronal apoptosis in neurodegenerative disorders Qiao et al, 2018;Wu et al, 2018;Xiao et al, 2017). Therefore, autophagy in neurons appears to be delicately modulated and whether it is beneficial or harmful in neurological diseases depends on the balance between the amount of substrate and the capacity of the autophagy machinery (Yu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation

Cao

Liu

et al. 2019

British J Pharmacology

123

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Background and Purpose: Sleep deprivation compromises learning and memory in both humans and animals, and can be reversed by administration of modafinil, a drug promoting wakefulness. Dysfunctional autophagy increases activation of apoptotic cascades, ultimately leading to increased neuronal death, which can be alleviated by autophagy inhibitors. This study aimed to investigate the alleviative effect and mechanism of modafinil on the excessive autophagy occurring in the hippocampus of mice with deficiency of learning and memory induced by sleep deprivation. Experimental Approach: The Morris water maze was used to assess the effects of modafinil on male C57BL/6Slac mice after 48-hr sleep deprivation. The HT-22 hippocampal neuronal cell line was also used. Nissl staining, transmission electron microscope, immunofluorescence, Western blot, transient transfection, and autophagy inducer were used to study the effect and mechanism of modafinil on hippocampal neurons with excessive autophagy and apoptosis. Key Results: Modafinil improved learning and memory in sleep-deprived mice, associated with the inhibition of excessive autophage and apoptosis and an enhanced activation of the PI3K/Akt/mTOR/P70S6K signalling pathway in hippocampal neurons. These effects of modafinil were abolished by rapamycin. In addition, modafinil suppressed the aberrant autophagy and apoptosis induced by rapamycin and reactivated PI3K/Akt/mTOR/P70S6K signals in HT-22 cells. Conclusions and Implications: These results suggested that modafinil alleviated impaired learning and memory of sleep-deprived mice potentially by suppressing excessive autophagy and apoptosis of hippocampal neurons. This novel mechanism may add to our knowledge of modafinil in the clinical treatment of impaired memory caused by sleep loss.Abbreviations: DG, dentate gyrus; 3-MA, 3-methyladenine; mTOR, mammalian target of rapamycin; MWM, Morris water maze; p62, ubiquitin-binding protein p62 or sequestosome-1; P70S6K, ribosomal protein S6 kinase; p-Akt, phosphorylated PKB; p-P70S6K, phosphorylated ribosomal protein S6 kinase; p-PI3K, phosphorylated PI3K

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The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits

Cited by 61 publications

References 27 publications

The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

The Nootropic Drug Α-Glyceryl-Phosphoryl-Ethanolamine Exerts Neuroprotective Effects in Human Hippocampal Cells

Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice

Modafinil protects hippocampal neurons by suppressing excessive autophagy and apoptosis in mice with sleep deprivation

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