Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Nam, Hyeri; Lee, Younghwan; Kim, Boil; Lee, Ji-Won; Hwang, Seohyeon; An, Hailong; Chung, Kyung Min; Park, Youngjin; Hong, Jihyun; Kim, Kyungjin; Kim, Eunkyoung; Choe, Han Kyoung; Yu, Seong‐Woon

doi:10.1038/s41467-022-29653-2

Cited by 15 publications

(19 citation statements)

References 72 publications

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“…Our results are consistent with previous data reporting increased IL-18 secretion from activated mouse microglia (86) and increased levels of IL-18 and MIF within the brains and cerebrospinal fluid of AD patients, respectively (87, 88). In contrast to our findings, and these findings from human AD tissue, cultured microglia from PSEN2 (N141I) knock-in mice exhibited a different range of chemokine release in response to Aβ 42 not impacted in our PSEN2 (N141I)-derived microglia such as the significant upregulation of CCL2, CCL5 and CXCL1 (63). Single-cell transcriptomic analysis highlight substantial species differences in microglial expression profiles and AD-associated genes such as PSEN (89, 90).…”

Section: Discussioncontrasting

confidence: 99%

“…Upon activation, microglia transition into a reactive morphology whereby the cells become less ramified through shorter and less complex processes (59), a characteristic observed in AD mouse models and in mice following ischemic injury (60)(61)(62). Similarly, PSEN2 (N141I) knock-in mice exhibited microglia with decreased ramification and number of dendritic branches, however no change in the branch length was observed (63,64). Despite PSEN2 (N141I)mutant microglia presenting with some morphological characteristics consistent with activation, namely reduced ramification, they do not entirely recapture the archetypal phenotype associated with microglial activation and suggest a more subtle change in phenotype.…”

Section: Discussionmentioning

confidence: 99%

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iPSC-Derived PSEN2 (N141I) Astrocytes and Microglia Exhibit a Primed Inflammatory Phenotype

Sullivan

Lane

Ball

et al. 2022

Preprint

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Background: Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimers disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. Methods: iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently labelled fibrillar Aβ42. Results: AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β ; and increased secretion and phagocytosis of Aβ42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells show exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. Conclusion: Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a primed phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ42 production and phagocytosis.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

iPSC-Derived PSEN2 (N141I) Astrocytes and Microglia Exhibit a Primed Inflammatory Phenotype

Sullivan

Lane

Ball

et al. 2022

Preprint

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“…First, while Aβ processing is aberrant in both the PSEN1 and PSEN2 mutations, the proximity of presenilin-containing gamma secretase complexes to APP pools likely plays a role in the levels of Aβ peptide species as well as the processing of alternative substrates. Second, while neurons are particularly affected by PSEN1 mutations, PSEN2 may be the preferential gamma secretase catalytic component in microglia [15,108,109]. These reports suggest that the in ammatory endotype modestly enriched in the PSEN2 N141I patient-derived neurons may be more apparent in the canonically in ammatory microglia cell type.…”

Section: Discussionmentioning

confidence: 92%

Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease

Valdes

Caldwell

Liu

et al. 2022

Preprint

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Background Mutations in PSEN1, PSEN2, and APP can lead to Alzheimer’s disease (AD) with an early age at onset (AAO) and hallmark progressive cognitive decline. These mutations are highly penetrant. Although mutations in PSEN1 are more common and usually have an earlier AAO, certain mutations in PSEN1 cause a later AAO, similar to PSEN2 and APP mutations. We sought to determine whether common disease endotypes exist across these mutations with a relatively late AAO. Methods We generated hiPSC-derived neurons from patients harboring autosomal-dominant, familial Alzheimer’s disease (FAD) mutations in PSEN1, PSEN2, and APP with a documented age at onset (AAO) around 55 years: PSEN1A79V, PSEN2N141I, and APPV717I. We carried out RNA-seq and ATAC-seq to mechanistically characterize the gene expression and chromatin accessibility changes, respectively. Differential expression analysis, enrichment analysis, TF activity identification, and co-expression module detection were performed for RNA-seq. Differential peak analysis and annotation, TF motif footprinting and differential motif accessibility, and peak functional enrichment were performed for ATAC-seq. This approach allowed us to identify the correlation between gene expression and chromatin accessibility associated with key disease endotypes. Results Using a multiomics approach, we identify and characterize common endotypes in mutations across all three FAD genes: dedifferentiation of a mature neuron to a less differentiated quasi-neuron state, dysregulation of synaptic signaling, repression of mitochondrial function and metabolism, and inflammation. The integrativeanalysis allowed us to ascertain the master transcriptional regulators associated with these endotypes, including REST, ASCL1, and ZIC family members (activation), as well as NRF1 (repression). Conclusions Our findings characterize the common regulatory changes within endotypes across these FAD mutations. However, the severity of dysregulation often differs between PSEN1, PSEN2, and APP mutations both in magnitude and direction. The overarching common link between mutations in FAD genes is the reversion to a less-differentiated neuron state. The transcriptional regulatory mechanisms described within disease endotypes offer potential targets for therapeutic interventions.

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“…Innate immunity plays a major immune role in AD ( Heppner et al, 2015 ). Innate immune cell hyperexcitability was reported to be associated with cognitive decline ( Nam et al, 2022 ). In a murine amyloidosis model, IFN-I signaling represents a critical module within the neuroinflammatory network of AD and prompts concerted cellular states that are detrimental to memory and cognition ( Roy et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Landscape of immune infiltration in entorhinal cortex of patients with Alzheimerʼs disease

Zhang

Cao

et al. 2022

Front. Pharmacol.

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Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and manifests as progressive memory loss and cognitive dysfunction. Neuroinflammation plays an important role in the development of Alzheimer’s disease and anti-inflammatory drugs reduce the risk of the disease. However, the immune microenvironment in the brains of patients with Alzheimer’s disease remains unclear, and the mechanisms by which anti-inflammatory drugs improve Alzheimer’s disease have not been clearly elucidated. This study aimed to provide an overview of the immune cell composition in the entorhinal cortex of patients with Alzheimer’s disease based on the transcriptomes and signature genes of different immune cells and to explore potential therapeutic targets based on the relevance of drug targets. Transcriptomics data from the entorhinal cortex tissue, derived from GSE118553, were used to support our study. We compared the immune-related differentially expressed genes (irDEGs) between patients and controls by using the limma R package. The difference in immune cell composition between patients and controls was detected via the xCell algorithm based on the marker genes in immune cells. The correlation between marker genes and immune cells and the interaction between genes and drug targets were evaluated to explore potential therapeutic target genes and drugs. There were 81 irDEGs between patients and controls that participated in several immune-related pathways. xCell analysis showed that most lymphocyte scores decreased in Alzheimer’s disease, including CD4+ Tc, CD4+ Te, Th1, natural killer (NK), natural killer T (NKT), pro-B cells, eosinophils, and regulatory T cells, except for Th2 cells. In contrast, most myeloid cell scores increased in patients, except in dendritic cells. They included basophils, mast cells, plasma cells, and macrophages. Correlation analysis suggested that 37 genes were associated with these cells involved in innate immunity, of which eight genes were drug targets. Taken together, these results delineate the profile of the immune components of the entorhinal cortex in Alzheimer’s diseases, providing a new perspective on the development and treatment of Alzheimer’s disease.

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Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Cited by 15 publications

References 72 publications

iPSC-Derived PSEN2 (N141I) Astrocytes and Microglia Exhibit a Primed Inflammatory Phenotype

iPSC-Derived PSEN2 (N141I) Astrocytes and Microglia Exhibit a Primed Inflammatory Phenotype

Integrative multiomics reveals common endotypes across PSEN1, PSEN2, and APP mutations in familial Alzheimer’s disease

Landscape of immune infiltration in entorhinal cortex of patients with Alzheimerʼs disease

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