Gender-dependent accumulation of ceramides in the cerebral cortex of the APPSL/PS1Ki mouse model of Alzheimer’s disease

Barrier, Laurence; Ingrand, Sabrina; Fauconneau, Bernard; Page, Guylène

doi:10.1016/j.neurobiolaging.2008.10.011

Cited by 33 publications

(49 citation statements)

References 50 publications

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“…Exogeneous Cer has previously been shown to increase the half-life of BACE1 and promote the production of Aβ in human neuroglioma cells and Chinese hamster ovary cells (Puglielli et al, 2003). In addition, the level of Cer was observed to increase in different regions of the brain in both AD patients (Han et al, 2002;He et al, 2010;Chan et al, 2012;Filippov et al, 2012) and mouse model of AD (Barrier et al, 2010). In PS1/PS2 deficiency mouse embryonic fibroblast cells, increased level of SM was observed with reduction in the activity of neutral sphingomyelinase (nSMase).…”

Section: Lipid Changes Related To Amyloid β-Induced Ad Pathologymentioning

confidence: 99%

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

Xiang

Lam

Shui

2015

Biological Chemistry

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Lipids serve many distinct functions in cellular homeostasis such as membrane organization, as a platform for membrane function and protein/protein or protein/lipid interaction, energy storage, as well as secondary messengers in signal transduction. Perturbations in lipid homeostasis may result in abnormal cellular function. Alzheimer's disease (AD) is a neurodegenerative disorder in which the brain represents the primary site of pathology. While there is a plethora of previous work pertaining to AD pathogenesis, the precise mechanism of the disease is still not well-understood. Recent waves of technological advances in the realm of lipidomics have enabled scientists to look at AD pathogenesis from a previously unexplored perspective, and studies have revealed extensive lipid aberrations are implicated in the disease pathology. Herein, we review the critical lipids alternations, which affect amyloid plaque and neurofibrillary tangles formation and accumulation, as well as lipid aberrations related to neuronal and synaptic dysfunction in cells and animal models. We also summarize lipid abnormalities observed in the human cerebrospinal fluid (CSF), as well as other circulating fluids including plasma and serum in association with AD, which could serve as candidate biomarkers to diagnose and monitor the disease.

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Section: Lipid Changes Related To Amyloid β-Induced Ad Pathologymentioning

confidence: 99%

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

Xiang

Lam

Shui

2015

Biological Chemistry

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“…The cells were broken on ice with 50 to 100 strokes of a small glass Dounce homogenizer (checking cells under a light microscope to ensure that they were broken). The suspension was then centrifuged by guest, on May 10, 2018 www.jlr.org Downloaded from level availability of substrate becomes rate-limiting for product formation, as illustrated for the CerS2-driven reaction in Fig. 1C .…”

Section: Preparation Of Cell or Tissue Homogenatesmentioning

confidence: 99%

“…A disadvantage with the fl uorescent format is that the signal can fade under laboratory lights if adequate precautions are not taken to protect the samples from light. TLC-based methods are able to distinguish long chain (C14-C18) from very long chain (C22-C26) ceramide and dihydroceramide but cannot clearly distinguish C16:0 from C18:0 or C24:0 from C24:1 dihydroceramde, for example ( 16,23 ). Although this is a drawback with any TLC-based approach, the appearance of a product band in our assay is dependent on provision of a particular fatty acid-CoA substrate ( Figs.…”

mentioning

confidence: 95%

A fluorescent assay for ceramide synthase activity

Kim

Qiao

Toop

et al. 2012

Journal of Lipid Research

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“…Therefore, we worked only with 3-month-old mice to examine abnormalities of death receptor signaling before neuronal loss. Experiments were performed with the cortex, where we showed a strong intraneuronal A␤ accumulation and diffuse amyloid deposits at this age (27) and because the cortex offers sufficient material for all assays. In Fig.…”

Section: Physical Interaction Between Pkr and Fadd In A␤42-treated Shmentioning

confidence: 99%

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

Couturier

Morel

Pontcharraud

et al. 2010

Journal of Biological Chemistry

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Alzheimer Disease (AD)2 is the leading cause of dementia in the elderly, affecting 25 million people in the world with about 5% of genetic origin. The biological features of AD are neuronal loss, senile plaques predominantly composed of amyloid ␤ peptide (A␤), and the presence of neurofibrillary tangles, leading to a progressive deterioration of cognitive function with loss of memory. Unfortunately, no definitive therapy for AD exists.The involvement of A␤ is clearly established, but mechanisms that underlie neuronal death are currently under investigation. For 10 years, research has focused on pathways controlling translation (1-5). They revealed that activated double-stranded RNA-dependent protein kinase (PKR), which phosphorylates the ␣-subunit of eIF2, was associated with degenerating neurons in AD brains (6 -8). Furthermore, the levels of phosphorylated forms of PKR and eIF2␣ were significantly increased in AD cellular models exposed to A␤42 (2, 5) in the brain of AD transgenic mice (1, 9) and in lymphocytes of AD patients (10). These modifications were negatively correlated with cognitive and memory test scores performed in AD patients (3, 10, 11). Besides its important role as a translational regulator, PKR is a key mediator in different signaling pathways. Indeed, among its downstream targets, the Fas-associated protein with a death domain (FADD) and subsequent caspase-8 are responsible for PKR-induced apoptosis in virus-infected cells (12). Furthermore, the overexpression of a dominant-negative FADD construct rescued SH-SY5Y cells from either tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or A␤-induced neurotoxicity (13). FADD could be involved in apoptosis through its nuclear localization by interacting with the methylCpG binding domain protein 4 (MDB4), a protein known to be implicated in DNA repair, but that could promote apoptosis when associated with FADD (14). Furthermore, many postmortem studies have reported the role of the FADD-linked death receptor signaling pathway in the pathobiology of AD (15-17).However, control of FADD under the PKR activation in AD remains unknown. The present study performed a detailed analysis of PKR and FADD interaction in A␤-treated cells and in APP SL PS1 KI transgenic mice. The purpose is to determine if inhibition of PKR could reduce apoptosis through the decrease in this death adaptor activation. Here, we showed a physical interaction between PKR and FADD in nuclei of A␤42-treated SH-SY5Y and in APP SL PS1 KI mice. Furthermore, PKR inhibitory treatments prevented not only the nuclear translocation of FADD but also significantly decreased caspase-3 and -8 activities induced by A␤ neurotoxicity. EXPERIMENTAL PROCEDURES

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Gender-dependent accumulation of ceramides in the cerebral cortex of the APPSL/PS1Ki mouse model of Alzheimer’s disease

Cited by 33 publications

References 50 publications

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

A fluorescent assay for ceramide synthase activity

Interaction of Double-stranded RNA-dependent Protein Kinase (PKR) with the Death Receptor Signaling Pathway in Amyloid β (Aβ)-treated Cells and in APPSLPS1 Knock-in Mice

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