Cells

26 pages, 652 KiB

Open AccessReview

From Genetics to Neuroinflammation: The Impact of ApoE4 on Microglial Function in Alzheimer’s Disease

by Daniela Dias, Camila Cabral Portugal, João Relvas and Renato Socodato

Cells 2025, 14(4), 243; https://doi.org/10.3390/cells14040243 - 7 Feb 2025

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder marked by progressive cognitive decline and memory loss, impacting millions of people around the world. The apolipoprotein E4 (ApoE4) allele is the most prominent genetic risk factor for late-onset AD, dramatically increasing disease susceptibility and [...] Read more.

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder marked by progressive cognitive decline and memory loss, impacting millions of people around the world. The apolipoprotein E4 (ApoE4) allele is the most prominent genetic risk factor for late-onset AD, dramatically increasing disease susceptibility and accelerating onset compared to its isoforms ApoE2 and ApoE3. ApoE4’s unique structure, which arises from single-amino-acid changes, profoundly alters its function. This review examines the critical interplay between ApoE4 and microglia—the brain’s resident immune cells—and how this relationship contributes to AD pathology. We explore the molecular mechanisms by which ApoE4 modulates microglial activity, promoting a pro-inflammatory state, impairing phagocytic function, and disrupting lipid metabolism. These changes diminish microglia’s ability to clear amyloid-beta peptides, exacerbating neuroinflammation and leading to neuronal damage and synaptic dysfunction. Additionally, ApoE4 adversely affects other glial cells, such as astrocytes and oligodendrocytes, further compromising neuronal support and myelination. Understanding the ApoE4–microglia axis provides valuable insights into AD progression and reveals potential therapeutic targets. We discuss current strategies to modulate ApoE4 function using small molecules, antisense oligonucleotides, and gene editing technologies. Immunotherapies targeting amyloid-beta and ApoE4, along with neuroprotective approaches to enhance neuronal survival, are also examined. Future directions highlight the importance of personalized medicine based on individual ApoE genotypes, early biomarker identification for risk assessment, and investigating ApoE4’s role in other neurodegenerative diseases. This review emphasizes the intricate connection between ApoE4 and microglial dysfunction, highlighting the necessity of targeting this pathway to develop effective interventions. Advancing our understanding in this area holds promise for mitigating AD progression and improving outcomes for those affected by this relentless disease. Full article

(This article belongs to the Special Issue Glial Cells in Aging Neuroscience)

22 pages, 5201 KiB

Open AccessArticle

Promegestone Prevents Lipopolysaccharide-Induced Cervical Remodeling in Pregnant Mice

by Amna Nadeem, Lubna Nadeem, Stephen James Lye and Oksana Shynlova

Cells 2025, 14(4), 242; https://doi.org/10.3390/cells14040242 (registering DOI) - 7 Feb 2025

Abstract

In most mammals, a withdrawal of the pro-gestational hormone progesterone (P4) is necessary for labor onset. In murine cervix, P4 withdrawal is mediated by enzymes steroid 5-alpha-reductase type 1 (SRD5A1) and 20-alpha-hydroxysteroid-dehydrogenase (20α-HSD). Previously, we have shown that inflammatory stimuli induce 20α-HSD levels [...] Read more.

In most mammals, a withdrawal of the pro-gestational hormone progesterone (P4) is necessary for labor onset. In murine cervix, P4 withdrawal is mediated by enzymes steroid 5-alpha-reductase type 1 (SRD5A1) and 20-alpha-hydroxysteroid-dehydrogenase (20α-HSD). Previously, we have shown that inflammatory stimuli induce 20α-HSD levels in uterine muscle (myometrium). Here, we hypothesized that (1) infectious inflammation alters the levels of both P4-metabolizing enzymes in mouse cervix, which consequently ceases P4-mediated inhibition of cervical remodeling, thereby inducing preterm labor (PTL); (2) a progestin, selective progesterone receptor modulator promegestone (aka R5020), non-metabolizable by 20α-HSD, can block lipopolysaccharide (LPS)-induced PTL in mice by maintaining P4 signaling and preventing cervical remodeling. Using RT-PCR and IHC/IF methods, we evaluated the effect of inflammation on the expression of both enzymes in mouse cervix and determined if R5020 can prevent cervical remodeling and PTL in mice. We found significant induction of SRD5A1 and 20α-HSD proteins (p < 0.01), as well as transcript levels of pro-inflammatory cytokines Il1b, Il6, chemokines Cxcl1, Ccl2, cervical ripening enzyme Has2, hyaluronic acid binding protein/HABP (p < 0.05), and a simultaneous decrease in major extracellular fibrillar proteins, collagen type 1 and type 3 (col1a1, col3a1), in mouse cervix during PTL. The prophylactic administration of R5020 in pregnant mice significantly inhibited cervical remodeling and prevented PTL irrespective of the route of LPS-induction, systemic or local. We concluded that R5020 is a promising novel drug application for preterm birth prevention. Full article

(This article belongs to the Section Reproductive Cells and Development)

21 pages, 2142 KiB

Open AccessArticle

Effects of Microplastic Accumulation on Neuronal Death After Global Cerebral Ischemia

by Dong Yeon Kim, Min Kyu Park, Hyun Wook Yang, Seo Young Woo, Hyun Ho Jung, Dae-Soon Son, Bo Young Choi and Sang Won Suh

Cells 2025, 14(4), 241; https://doi.org/10.3390/cells14040241 - 7 Feb 2025

Abstract

Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to a stroke due to blocked or unstable blood vessels. Global cerebral ischemia (GCI), characterized by an interruption in blood flow, deprives the brain of oxygen and nutrients, [...] Read more.

Brain ischemia, a condition in which the brain is deprived of blood flow, can lead to a stroke due to blocked or unstable blood vessels. Global cerebral ischemia (GCI), characterized by an interruption in blood flow, deprives the brain of oxygen and nutrients, producing reactive oxygen species (ROS) that trigger cell death, which kills nerve cells. Microplastics (MPs), tiny environmental pollutants, can enter the human body through contaminated food, water, disposable items, cosmetics, and more. Once in the brain, MPs can increase neuroinflammation by overstimulating inflammatory factors such as microglia. MPs can also damage neurons by scratching myelin and microtubules, slowing signal transduction, causing cognitive impairment, and leading to neuronal death. Furthermore, microtubule damage may result in the release of phosphorylated tau proteins, potentially linked to Alzheimer’s disease. We hypothesized that MPs could exacerbate neuroinflammation and microtubule destruction after GCI, leading to increased neuronal death. To test this hypothesis, we administered MPs (0.5 µm) orally at a dose of 50 mg/kg before and after inducing GCI. Staining techniques such as Fluoro-Jade B (FJB), ionized calcium-binding adaptor molecule 1 (Iba-1), cluster of differentiation 68 (CD68), myelin basic protein (MBP), and microtubule-associated protein 2 (MAP2) were used, along with Western blot analysis for interleukin-6 (IL-6), TNF-α, tau-5, and phospho-tau (S396) to evaluate the effects of MPs on neuronal cell death, neuroinflammation, and microtubule destruction. The results showed that MP accumulation significantly increased neuroinflammation, microtubule disruption, and neuronal cell death in the GCI-MP group compared to the GCI-vehicle group. Therefore, this study suggests that MP accumulation in daily life may contribute to the exacerbation of the disease, potentially leading to severe neuronal cell death after GCI. Full article

(This article belongs to the Special Issue Cell Stress and Intervention in Neurological Disease)

14 pages, 1346 KiB

Open AccessReview

Caspase-8: Arbitrating Life and Death in the Innate Immune System

by Sahil Gupta, Monica Aida Lopez, Amin M. Ektesabi, James N. Tsoporis, Chirag M. Vaswani, Shil Y. Gandhi, Gregory D. Fairn, Claudia C. Dos Santos and John C. Marshall

Cells 2025, 14(4), 240; https://doi.org/10.3390/cells14040240 - 7 Feb 2025

Abstract

Abstract: The canonical function of caspase-8 is to control timely cellular apoptosis to maintain tissue homeostasis and clear dysfunctional cells; however, emerging findings reveal novel, non-canonical roles of caspase in addition to regulating cellular apoptosis, including inflammatory response regulation, immune function, and cell [...] Read more.

Abstract: The canonical function of caspase-8 is to control timely cellular apoptosis to maintain tissue homeostasis and clear dysfunctional cells; however, emerging findings reveal novel, non-canonical roles of caspase in addition to regulating cellular apoptosis, including inflammatory response regulation, immune function, and cell differentiation. Furthermore, the functional versatility of caspase-8 is reported to be contingent on the presence and dimerization of various isoforms, which are produced through alternative splicing, altering its function and protein–protein interactions. Equally important are post-translational modifications, including phosphorylation and ubiquitination, which can act as a nexus to control caspase-8 activity and cellular localization. Here, we review the alternative splicing and post-translational modifications made to caspase-8 and discuss their influence on its canonical and non-canonical roles. Full article

(This article belongs to the Section Cell Signaling)

15 pages, 807 KiB

Open AccessReview

ATP-Dependent Chromatin Remodeler CSB Couples DNA Repair Pathways to Transcription with Implications for Cockayne Syndrome and Cancer Therapy

by Rabeya Bilkis, Robert J. Lake and Hua-Ying Fan

Cells 2025, 14(4), 239; https://doi.org/10.3390/cells14040239 - 7 Feb 2025

Viewed by 81

Abstract

Efficient DNA lesion repair is crucial for cell survival, especially within actively transcribed DNA regions that contain essential genetic information. Additionally, DNA breaks in regions of active transcription are prone to generating insertions and deletions, which are hallmark features of cancer genomes. Cockayne [...] Read more.

Efficient DNA lesion repair is crucial for cell survival, especially within actively transcribed DNA regions that contain essential genetic information. Additionally, DNA breaks in regions of active transcription are prone to generating insertions and deletions, which are hallmark features of cancer genomes. Cockayne syndrome protein B (CSB) is the sole ATP-dependent chromatin remodeler that is essential for coupling DNA repair pathways with transcription, leading to more efficient DNA repair in regions of active transcription. CSB is best known for its essential function in transcription-coupled nucleotide excision repair (TC-NER), a process that rapidly removes helix-distorting DNA lesions that stall RNA polymerase II, such as those created by chemotherapeutic platinum compounds and UV irradiation. In addition to NER, CSB has also been reported to couple homologous recombination to transcription. Most recently, CSB has also been shown to couple single-strand DNA break repair to transcription. In this review, we will discuss the overlapping and distinct mechanisms by which CSB couples these different DNA repair pathways to transcription. We will also discuss how these CSB functions may account for Cockayne syndrome and the emerging roles of CSB as an innovative target for cancer therapy. Full article

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13 pages, 1615 KiB

Open AccessReview

Treatment Response in Individual Organs Affected by Chronic Graft-Versus-Host Disease

by Takanobu Morishita, Paul J. Martin and Yoshihiro Inamoto

Cells 2025, 14(4), 238; https://doi.org/10.3390/cells14040238 - 7 Feb 2025

Viewed by 112

Abstract

Chronic graft-versus-host disease (GVHD) occurs in 30–70% of patients after allogeneic hematopoietic cell transplantation (HCT) and increases the risks of morbidity and mortality. Systemic corticosteroids are the standard initial treatment, but one-third of patients require subsequent treatment with other systemic agents. Treatment decisions [...] Read more.

Chronic graft-versus-host disease (GVHD) occurs in 30–70% of patients after allogeneic hematopoietic cell transplantation (HCT) and increases the risks of morbidity and mortality. Systemic corticosteroids are the standard initial treatment, but one-third of patients require subsequent treatment with other systemic agents. Treatment decisions are often based on physicians’ experience. The expected treatment response rates in specific organs affected by chronic GVHD may inform such decisions. In this review, we identify 20 studies reporting treatment response rates in individual organs according to objective criteria, summarize the results, discuss the caveats in data interpretation, identify the unmet needs, and suggest future directions in the field. For cutaneous sclerosis, we observed large discrepancies in organ response rates according to the current NIH criteria and patient-reported improvement, highlighting the need for better measurement tools. High response rates for lung involvement with certain novel drugs deserve further investigation. Full article

(This article belongs to the Special Issue State of the Art and Future Prospects in Stem Cell Transplantation)

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20 pages, 3963 KiB

Open AccessArticle

NE-MTOC Formation in Skeletal Muscle Is Mbnl2-Dependent and Occurs in a Sequential and Gradual Manner

by Payel Das, Robert Becker, Silvia Vergarajauregui and Felix B. Engel

Cells 2025, 14(4), 237; https://doi.org/10.3390/cells14040237 - 7 Feb 2025

Viewed by 314

Abstract

Non-centrosomal microtubule-organizing centers (ncMTOCs) are important for the function of differentiated cells. Yet, ncMTOCs are poorly understood. Previously, several components of the nuclear envelope (NE)-MTOC have been identified. However, the temporal localization of MTOC proteins and Golgi to the NE and factors controlling [...] Read more.

Non-centrosomal microtubule-organizing centers (ncMTOCs) are important for the function of differentiated cells. Yet, ncMTOCs are poorly understood. Previously, several components of the nuclear envelope (NE)-MTOC have been identified. However, the temporal localization of MTOC proteins and Golgi to the NE and factors controlling the switch from a centrosomal MTOC to a ncMTOC remain elusive. Here, we utilized the in vitro differentiation of C2C12 mouse myoblasts as a model system to study NE-MTOC formation. We find based on longitudinal co-immunofluorescence staining analyses that MTOC proteins are recruited in a sequential and gradual manner to the NE. AKAP9 localizes with the Golgi to the NE after the recruitment of MTOC proteins. Moreover, siRNA-mediated depletion experiments revealed that Mbnl2 is required for proper NE-MTOC formation by regulating the expression levels of AKAP6β. Finally, Mbnl2 depletion affects Pcnt isoform expression. Taken together, our results shed light on how mammals post-transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify Mbnl2 as a novel modulator of ncMTOCs in skeletal muscle cells. Full article

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Cells, Volume 14, Issue 4 (February-2 2025) – 7 articles

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