Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer’s Disease and Other Neurodegenerative Diseases

Custodia, Antía; Romaus-Sanjurjo, Daniel; Aramburu-Núñez, Marta; Álvarez-Rafael, Diego; Vázquez‐Vázquez, Laura; Camino-Castiñeiras, Javier; Leira, Yago; Pías‐Peleteiro, Juan Manuel; Aldrey, José Manuel; Sobrino, Tomás; Ouro, Alberto

doi:10.3390/ijms23158082

Cited by 11 publications

(8 citation statements)

References 194 publications

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“…MERCS are involved in the production of ceramides, core constituents of sphingolipids important for the regulation of cell growth, differentiation, cell-cycle arrest, cell survival, apoptosis, and inflammation [ 22 ]. Specifically, increased levels of ceramides Cer16, Cer18, Cer20, and Cer24 in the blood of AD patients were directly linked to oxidative stress and Aβ pathology [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Panes

Oanh

Gao

et al. 2023

Cells

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Alzheimer’s disease (AD) has no cure. Earlier, we showed that partial inhibition of mitochondrial complex I (MCI) with the small molecule CP2 induces an adaptive stress response, activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, Aβ and pTau accumulation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD. Here, using serial block-face scanning electron microscopy (SBFSEM) and three-dimensional (3D) EM reconstructions combined with Western blot analysis and next-generation RNA sequencing, we demonstrate that CP2 treatment also restores mitochondrial morphology and mitochondria-endoplasmic reticulum (ER) communication, reducing ER and unfolded protein response (UPR) stress in the APP/PS1 mouse brain. Using 3D EM volume reconstructions, we show that in the hippocampus of APP/PS1 mice, dendritic mitochondria primarily exist as mitochondria-on-a-string (MOAS). Compared to other morphological phenotypes, MOAS have extensive interaction with the ER membranes, forming multiple mitochondria-ER contact sites (MERCS) known to facilitate abnormal lipid and calcium homeostasis, accumulation of Aβ and pTau, abnormal mitochondrial dynamics, and apoptosis. CP2 treatment reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reductions in MERCS, ER/UPR stress, and improved lipid homeostasis. These data provide novel information on the MOAS-ER interaction in AD and additional support for the further development of partial MCI inhibitors as a disease-modifying strategy for AD.

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Section: Introductionmentioning

confidence: 99%

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Panes

Oanh

Gao

et al. 2023

Cells

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“…Therefore, even minor changes in CER metabolism in response to various stimuli are decisive for cellular fate [50]. The imbalance of SL species due to dysregulation of SL metabolism is a common event in AD [49]. A study showed that brain CER levels of Alzheimer's patients increased compared to neurologically normal controls of the same age.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Oxidative Stress and Apoptosis by Alteration of Bioactive Lipids in The Pancreas, and Effect of Zinc Chelation in a Rat Model of Alzheimer's Disease

Acun,

Kantar

2024

Preprint

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Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer's disease (AD). It is known that peripheral insulin resistance in the early stages of AD precedes and is a precursor to amyloid-β (Aβ) deposition. Although it is known that improving the CNS insulin sensitivity of AD patients is an important therapeutic goal and that the majority of insulin in the brain comes from the periphery, there has been little attention to the changes that occur in the pancreatic tissue of AD patients. Therefore, it is crucial to elucidate the mechanisms affecting insulin resistance in pancreatic tissue in AD. It is known that zinc (Zn+2) chelation is effective in reducing peripheral insulin resistance, cell apoptosis, cell death, and oxidative stress. Aims: This study aimed to determine the bioactive lipids in the pancreas in the Aβ oligomer-induced rat model to determine the changes in amylin (AIPP), oxidative stress, and apoptosis in pancreatic cells and to reveal the therapeutic effect of the Cyclo-Z agent on them. AD and ADC rats were intracerebroventricular (i.c.v.) Aβ1-42 oligomers. Cyclo-Z gavage was applied to ADC and SHC rats for 21 days. First of all, the effects of AIPP, bioactive ceramides, apoptosis and oxidative stress on the pancreatic tissue of AD group rats were evaluated. Then, the effect of Cyclo-Z treatment on these was examined. ELISA kit was used in biochemical analyses. AIPP and ceramide (CER) levels and CER/ sphingosine-1 phosphate (S1P) ratio were increased in the pancreatic tissue of AD rats. It also increased the level of CER kinase (CERK), which is known to increase the concentration of CER 1-phosphate (C1P), which is known to be toxic to cells in the presence of excessive CER concentration. Due to the increase in CER level, it was observed that apoptosis and oxidative stress increased in the pancreatic cells of AD group rats. Cyclo-Z, which has Zn+2 chelating properties, reduced AD model rats' AIPP level and oxidative stress and could prevent pancreatic apoptosis. Similar therapeutic effects were not observed in the pancreatic tissue of Cyclo-Z administered to the SH group. For this reason, it is thought that Cyclo-Z agent may have a therapeutic effect on the peripheral hyperinsulinemia observed in the early stages of AD disease and the resulting low amount of insulin transported to the brain, by protecting pancreatic cells from apoptosis and oxidative stress by regulating their bioactive metabolites.

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“…Indeed, the sphingomyelin probe lysenin has recently contributed greatly to our understanding of the role of sphingomyelin (and indirectly ceramide) in membrane repair and antigen cytosol transfer in dendritic cells [ 93 , 94 , 95 ], and future studies analyzing the behavior of the KSR-based probes to membrane-disrupting stimuli may reveal new insights in the role of ceramide in membrane repair [ 96 ] and ceramide-mediated cell death [ 97 ]. Moreover, in addition to the role of KSR1 itself to RAS-mediated oncogenesis and its potential as a novel anti-cancer target [ 78 ], sphingolipid dysregulation has been linked to several cardiovascular, metabolic, and neurodegenerative diseases [ 98 , 99 ]. Thus, the KSR-based probes described here could contribute not only to a greater understanding of the pathophysiology underlying these diseases, but they may also help identify and characterize novel compounds and methods for future diagnostic or therapeutic clinical use.…”

Section: Discussionmentioning

confidence: 99%

Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis

Girik,

van Ek,

Dentand Quadri

et al. 2024

IJMS

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Ceramides regulate phagocytosis; however, their exact function remains poorly understood. Here, we sought (1) to develop genetically encoded fluorescent tools for imaging ceramides, and (2) to use them to examine ceramide dynamics during phagocytosis. Fourteen enhanced green fluorescent protein (EGFP) fusion constructs based on four known ceramide-binding domains were generated and screened. While most constructs localized to the nucleus or cytosol, three based on the CA3 ceramide-binding domain of kinase suppressor of ras 1 (KSR1) localized to the plasma membrane or autolysosomes. C-terminally tagged CA3 with a vector-based (C-KSR) or glycine-serine linker (C-KSR-GS) responded sensitively and similarly to ceramide depletion and accumulation using a panel of ceramide modifying drugs, whereas N-terminally tagged CA3 (N-KSR) responded differently to a subset of treatments. Lipidomic and liposome microarray analysis suggested that, instead, N-KSR may preferentially bind glucosyl-ceramide. Additionally, the three probes showed distinct dynamics during phagocytosis. Despite partial autolysosomal degradation, C-KSR and C-KSR-GS accumulated at the plasma membrane during phagocytosis, whereas N-KSR did not. Moreover, the weak recruitment of C-KSR-GS to the endoplasmic reticulum and phagosomes was enhanced through overexpression of the endoplasmic reticulum proteins stromal interaction molecule 1 (STIM1) and Sec22b, and was more salient in dendritic cells. The data suggest these novel probes can be used to analyze sphingolipid dynamics and function in living cells.

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Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer’s Disease and Other Neurodegenerative Diseases

Cited by 11 publications

References 194 publications

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Partial Inhibition of Complex I Restores Mitochondrial Morphology and Mitochondria-ER Communication in Hippocampus of APP/PS1 Mice

Modulation of Oxidative Stress and Apoptosis by Alteration of Bioactive Lipids in The Pancreas, and Effect of Zinc Chelation in a Rat Model of Alzheimer's Disease

Development of Genetically Encoded Fluorescent KSR1-Based Probes to Track Ceramides during Phagocytosis

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