Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer’s Disease Model

Lutzenberger, Manuel; Burwinkel, Michael; Riemer, Constanze; Bode, Victoria; Baier, Michael

doi:10.1371/journal.pone.0134228

Cited by 5 publications

(3 citation statements)

References 52 publications

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“…In order to evaluate if oligomer composition is affected by the inoculation of Aβ osa in mice, we fractionated soluble and insoluble Aβ aggregates from the hippocampus by sarkosyl detergent extraction. Western blot analysis of sarkosyl-soluble fraction showed an increase of 15 kDa and 12KDa bands (also referred as 4-mer and 3-mer forms of Aβ oligomers [ 28 ]) in Aβ osa -inoculated animals (Fig. 7 a).…”

Section: Resultsmentioning

confidence: 99%

Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation

Célestine

Jacquier-Sarlin

Borel

et al. 2023

acta neuropathol commun

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Alzheimer’s disease (AD) is characterized by intracerebral deposition of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These peptides and proteins induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from non-mutated Aβ1-40 or Aβ1-42 peptides can increase Aβ depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aβ peptides with different structures. The Aβ Osaka (Aβosa mutation (E693Δ)) is located within the Aβ sequence and thus the Aβosa peptides have different structures and properties as compared to non-mutated Aβ1-42 peptides (Aβwt). Here, we wondered if a single exposure to this mutated Aβ can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation. To answer this question we inoculated Aβ1-42-bearing Osaka mutation (Aβosa) in the dentate gyrus of APPswe/PS1dE9 mice at the age of two months. Their cognition and cerebral connectivity were analyzed at 4 months post-inoculation by behavioral evaluation and functional MRI. Aβ pathology as well as synaptic density were evaluated by histology. The impact of Aβosa peptides on synaptic health was also measured on primary cortical neurons. Remarkably, the intracerebral administration of Aβosa induced cognitive and synaptic impairments as well as a reduction of functional connectivity between different brain regions, 4 months post-inoculation. It increased Aβ plaque depositions and increased Aβ oligomers. This is the first study showing that a single, sporadic event as Aβosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. It suggests that a single inoculation of Aβ regulates a large cascade of events for a long time. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation

Célestine

Jacquier-Sarlin

Borel

et al. 2023

acta neuropathol commun

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“…In this context our study shows for the first time that C/EBPδ is a potent repressor of SNCA transcription in neurons. Most previous studies show that C/EBPδ is predominantly an activator of gene transcription 33,47,48 . There are however examples of genes transcriptionally repressed by C/EBPδ such as THBS1 in astrocytes 49 , prolactin in pituitary prolactinoma cells 50 or ABCA1 in macrophages 51 .…”

Section: Discussionmentioning

confidence: 99%

CCAAT/enhancer binding protein δ is a transcriptional repressor of α-synuclein

et al. 2019

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α-Synuclein is the main component of Lewy bodies, the intracellular protein aggregates representing the histological hallmark of Parkinson's disease. Elevated α-synuclein levels and mutations in SNCA gene are associated with increased risk for Parkinson's disease. Despite this, little is known about the molecular mechanisms regulating SNCA transcription. CCAAT/enhancer binding protein (C/EBP) β and δ are b-zip transcription factors that play distinct roles in neurons and glial cells. C/EBPβ overexpression increases SNCA expression in neuroblastoma cells and putative C/EBPβ and δ binding sites are present in the SNCA genomic region suggesting that these proteins could regulate SNCA transcription. Based on these premises, the goal of this study was to determine if C/EBPβ and δ regulate the expression of SNCA. We first observed that αsynuclein CNS expression was not affected by C/EBPβ deficiency but it was markedly increased in C/EBPδ-deficient mice. This prompted us to characterize further the role of C/EBPδ in SNCA transcription. C/EBPδ absence led to the in vivo increase of αsynuclein in all brain regions analyzed, both at mRNA and protein level, and in primary neuronal cultures. In agreement with this, CEBPD overexpression in neuroblastoma cells and in primary neuronal cultures markedly reduced SNCA expression. ChIP experiments demonstrated C/EBPδ binding to the SNCA genomic region of mice and humans and luciferase experiments showed decreased expression of a reporter gene attributable to C/EBPδ binding to the SNCA promoter. Finally, decreased CEBPD expression was observed in the substantia nigra and in iPSC-derived dopaminergic neurons from Parkinson patients resulting in a significant negative correlation between SNCA and CEBPD levels. This study points to C/EBPδ as an important repressor of SNCA transcription and suggests that reduced C/EBPδ neuronal levels could be a pathogenic factor in Parkinson's disease and other synucleinopathies and C/EBPδ activity a potential pharmacological target for these neurological disorders.

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“…We fractionated soluble and insoluble Aβ aggregates from the hippocampus by sarkosyl detergent extraction. Western blot analysis of sarkosylsoluble fraction showed that inoculation of Aβ osa led to an increase of 15kDa and 12KDa bands (also referred as 4-mer and 3-mer forms of Aβ oligomers [21]) (Fig. 8A).…”

Section: Aβ Seeds Inoculation Modulates Aβ Oligomerization Patterns A...mentioning

confidence: 99%

Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

Célestine

Jacquier-Sarlin

Borel

et al. 2022

Preprint

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Background Alzheimer’s disease (AD) is characterized by intracerebral accumulation of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These lesions induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from synthetic or recombinant non-mutated Aβ1−40 or Aβ1−42 peptides can increase Aβ plaque depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aβ peptides with different structures. The Aβosa mutation (E693Δ) is located within the Aβ sequence and thus the Aβosa peptides have different structures and properties as compared to non-mutated Aβ1−42 peptides (Aβwt). Here, we wondered if a single exposure to this mutated Aβ can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation compared to non-mutated Aβ. Method To answer this question we inoculated Aβ1−42-bearing Osaka mutation (Aβosa) in the dentate gyrus of APPswe/PS1dE9 mice at the age of two months. The inoculated mice were analyzed at 4 months post-inoculation by cognitive evaluation and functional MRI to assess cerebral connectivity. Aβ and tau lesions as well as synaptic density were evaluated by histology. The impact of Aβosa peptides on synaptic health was also measured on primary cortical neurons. Results Remarkably, compared to Aβwt, the intracerebral administration of Aβosa induced cognitive impairments, synaptic impairments and a reduction of the connectivity between different brain regions, 4 months post-inoculation. Aβ plaque depositions but not tau lesions were increased and Aβ oligomeric patterns were modified. Conclusion This is the first study showing long-term functional toxicity of Aβ seeds. It shows that a single, sporadic event as Aβosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. Extrapolation of this discovery suggests that any event that modulates focally Aβ aggregation process in the time-course of AD can be responsible for the heterogeneity of AD clinical outcome.

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Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer’s Disease Model

Cited by 5 publications

References 52 publications

Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation

Long term worsening of amyloid pathology, cerebral function, and cognition after a single inoculation of beta-amyloid seeds with Osaka mutation

CCAAT/enhancer binding protein δ is a transcriptional repressor of α-synuclein

Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

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