Synaptic aging disrupts synaptic morphology and function in cerebellar Purkinje cells

Fan, Wei; Yan, M.; Wang, Lai; Yizheng, Sun; Deng, Jian

doi:10.4103/1673-5374.233445

Cited by 23 publications

(14 citation statements)

References 52 publications

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“…Lipotoxicity derived from excess cardiac ceramide accumulation contributes to obesity‐related dilated cardiomyopathy. Furthermore, chronic alcohol consumption has been reported to increase ceramide content in various cell types, such as hepatocytes and neurons (Lizarazo et al, 2013; Wang et al, 2013). In this study, the ceramide content in cardiac tissue was measured by a triple‐quadrupole mass spectrometer.…”

Section: Resultsmentioning

confidence: 99%

“…Ceramide accumulation in the myocardium has been documented in both rodent and human lipotoxic cardiomyopathy studies (Park et al, 2008). Furthermore, chronic alcohol consumption is associated with dysregulated ceramide metabolism in the liver, hippocampal dentate gyrus, and muscles (Lizarazo et al, 2013; Wang et al, 2013). However, the relationship between lipotoxicity and ceramides in alcoholic cardiomyocyte death remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4‐dependent pathway

Wang

Liu

et al. 2022

Alcoholism Clin & Exp Res

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Background and aims Excessive alcohol consumption predisposes drinkers to develop alcoholic cardiomyopathy. Although cardiomyocyte loss is the hallmark of cardiomyopathy, the underlying mechanism remains elusive. This study examined the potential mechanism of alcohol‐induced cardiomyocyte death in a mouse model of alcoholic cardiomyopathy. Methods We established the alcoholic cardiomyopathy mouse model using C57BL/6J mice and confirmed it via echocardiography and histological examination. The cardiac ceramide content and profile were analyzed with a triple‐quadrupole mass spectrometer. The molecular mechanism underlying the accumulation of ceramide due to chronic alcohol consumption and ceramide‐induced cardiomyocyte death were investigated by in vivo and in vitro models. Finally, we established a TLR4 mutation model to explore the function of TLR4 in CH3/HeJ mice. Results Cardiac lipotoxicity that followed alcohol exposure resulted mainly in C16:0‐, C18:0‐, and C24:1‐ceramide aggregation. Genes encoding the sphingosine hydrolysis enzymes (SMPD1 and SMPD2) rather than de novo synthetic biomarkers were markedly upregulated. Exogenous ceramide mimics (C6‐ceramide) werenderlying the accumulation of ceramide observed to cause H9C2 cardiomyocyte‐like cell death, which was consistent with results under palmate acid (PA) treatment. As a ceramide precursor, PA induces intracellular ceramide generation through TLR4 signaling, which can be abolished by an inhibitor of ceramide synthesis. Furthermore, mechanistic investigations demonstrated that pharmacological or genetic inhibition of TLR4 attenuated PA‐induced cell death and corresponding ceramide production. Moreover, global mutation of TLR4 in CH3/HeJ mice significantly reduced the accumulation of C24:0, C24:1, OH_C24:1, and total ceramide following alcohol challenge. Conclusions Our findings demonstrate that ceramide accumulation plays a crucial role in alcoholic cardiomyopathy, effects that are partially mediated through the TLR4‐dependent pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4‐dependent pathway

Wang

Liu

et al. 2022

Alcoholism Clin & Exp Res

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“…Synaptic degeneration can be caused by degenerative neurological diseases, such as Alzheimer's disease (Jaworski et al, 2011;Dominguez-Alvaro et al, 2018) and prion disease (Siskova et al, 2009;Caleo et al, 2012); it can also be caused by injuries, such as surgery, microwaves (Tan et al, 2017) and mild fluid percussion (Powell et al, 2018) and can occur in aging animals (Gillingwater et al, 2002;Fan et al, 2018). Fragmentation and degeneration of organelles exposes more proteins or polypeptides, which contain amino groups to which osmic acid can easily adsorb, resulting in electron density under an electron microscope.…”

Section: Discussion Ultrastructural Features Of Nmj Bouton Degenerati...mentioning

confidence: 99%

“…Presynaptic organelles appear swollen or dark and dense (Qi et al, 2017), and degenerating dendrites are also dark (Jaworski et al, 2011) during synapse degeneration. Once the synapse is degenerated, the PSD looks curved (Caleo et al, 2012), and both presynaptic and postsynaptic membranes have been shown to become thin in aging mice (Fan et al, 2018;Figures 1G,G"). During NMJ bouton degeneration in wild-type Drosophila, the complex SSR membrane became swollen and retracted until a few remnants were left, but more SSR remnants degenerated into fragments or thin slices in dnrx mutants (Figures 4, 5).…”

Section: Discussion Ultrastructural Features Of Nmj Bouton Degenerati...mentioning

confidence: 99%

“…Therefore, the stability of synaptic boutons is a dynamic balance among growth (Miyamoto et al, 2016), pruning, degeneration, and elimination processes. Synapse degeneration is a complicated process that includes retraction (Watts et al, 2003;Pielage et al, 2011) and degradation (Smith et al, 2013;Tan et al, 2017) of presynaptic and postsynaptic components, such as synaptic vesicles (Gillingwater et al, 2002;Siskova et al, 2009;Pielage et al, 2011;Qi et al, 2017;Fan et al, 2018;Pareek et al, 2018), microtubules (Awasaki et al, 2006), and postsynaptic density (Caleo et al, 2012). In most of synaptic degeneration, the degenerated ultrastructure shows the characteristics of dark electron density, which is very similar to the aging and death of organelles.…”

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confidence: 99%

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Neurexin and neuroligins jointly regulate synaptic degeneration at the Drosophila neuromuscular junction based on TEM studies

Guangming,

Mei,

Qinfeng

et al. 2023

Front. Cell. Neurosci.

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The Drosophila larval neuromuscular junction (NMJ) is a well-known model system and is often used to study synapse development. Here, we show synaptic degeneration at NMJ boutons, primarily based on transmission electron microscopy (TEM) studies. When degeneration starts, the subsynaptic reticulum (SSR) swells, retracts and folds inward, and the residual SSR then degenerates into a disordered, thin or linear membrane. The axon terminal begins to degenerate from the central region, and the T-bar detaches from the presynaptic membrane with clustered synaptic vesicles to accelerate large-scale degeneration. There are two degeneration modes for clear synaptic vesicles. In the first mode, synaptic vesicles without actin filaments degenerate on the membrane with ultrafine spots and collapse and disperse to form an irregular profile with dark ultrafine particles. In the second mode, clear synaptic vesicles with actin filaments degenerate into dense synaptic vesicles, form irregular dark clumps without a membrane, and collapse and disperse to form an irregular profile with dark ultrafine particles. Last, all residual membranes in NMJ boutons degenerate into a linear shape, and all the residual elements in axon terminals degenerate and eventually form a cluster of dark ultrafine particles. Swelling and retraction of the SSR occurs prior to degradation of the axon terminal, which degenerates faster and with more intensity than the SSR. NMJ bouton degeneration occurs under normal physiological conditions but is accelerated in Drosophila neurexin (dnrx) dnrx273, Drosophila neuroligin (dnlg) dnlg1 and dnlg4 mutants and dnrx83;dnlg3 and dnlg2;dnlg3 double mutants, which suggests that both neurexin and neuroligins play a vital role in preventing synaptic degeneration.

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Carnosine research in relation to aging brain and neurodegeneration: A blessing for geriatrics and their neuronal disorders

Banerjee

Poddar

2020

Archives of Gerontology and Geriatrics

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Synaptic aging disrupts synaptic morphology and function in cerebellar Purkinje cells

Cited by 23 publications

References 52 publications

Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4‐dependent pathway

Ectopic accumulation of ceramide in cardiomyocytes modulates alcoholic cardiomyopathy via the TLR4‐dependent pathway

Neurexin and neuroligins jointly regulate synaptic degeneration at the Drosophila neuromuscular junction based on TEM studies

Carnosine research in relation to aging brain and neurodegeneration: A blessing for geriatrics and their neuronal disorders

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