Single nuclei transcriptomics in diabetic mice reveals altered brain hippocampal endothelial cell function, permeability, and behavior

Nuthikattu, Saivageethi; Milenkovic, Dragan; Norman, Jennifer E.; Villablanca, Amparo C.

doi:10.1016/j.bbadis.2023.166970

Cited by 7 publications

(4 citation statements)

References 94 publications

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“…These insights support the idea that neuroinflammation and damage to endothelial cells and barriers, driven by T2DM, are critical in the cognitive deterioration linked to this condition. LncRNAs, functioning as regulatory molecules, could be crucial in this mechanism, presenting potential new targets for the treatment of VCI [ 126 ].…”

Section: The Role Of Lncrnas In Vcimentioning

confidence: 99%

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Fan,

Xiao,

Zhang

2024

Vaccines

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Vascular cognitive impairment (VCI) encompasses a wide range of cognitive disorders stemming from cerebrovascular issues, such as strokes or small vessel disease. These conditions often pose challenges to traditional diagnostic approaches due to their multifactorial nature and varied clinical presentations. Recently, next-generation sequencing (NGS) technologies have provided detailed analyses of long non-coding RNAs (lncRNAs) in the molecular pathobiology of VCI. These new findings help with molecular-based diagnostics and treatments of VCI. Within this realm, the concept of immune modulation, especially through specific vaccinations, emerges as a promising therapeutic strategy in VCI mitigation. In this review, we comprehensively elucidate the function of lncRNAs in VCI, emphasizing the advanced understanding of VCI’s molecular underpinnings made possible through NGS technologies. Significant focus is placed on the immune system’s role in VCI, particularly the neuroinflammatory processes which are consequential to cerebrovascular abnormalities. We believe that lncRNAs participate in regulating these immunological pathways, potentially guiding the development of vaccines targeting VCI. In this context, we propose a novel perspective: using knowledge about lncRNA profiles and functions to guide vaccine development, we can potentially exploit the body’s immune response to mitigate or prevent VCI. This approach has the potential to revolutionize VCI management by introducing targeted immunization strategies informed by molecular signatures, a concept that remains largely unexplored in current research endeavors. In addition, we summarize current progress and propose future directions, advocating for robust, interdisciplinary studies to validate the potential intersections between lncRNA landscapes, VCI pathology, and immunology. This review aims to spur innovative research and promote the development of lncRNA-informed vaccine strategies as proactive interventions against the cognitive consequences of VCI.

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Section: The Role Of Lncrnas In Vcimentioning

confidence: 99%

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Fan,

Xiao,

Zhang

2024

Vaccines

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“…Therefore, an increase in ceramide levels disrupts vascular endothelial function and increases vascular permeability ( Liu F. et al, 2022 ). Transcriptomic studies have uncovered neuroinflammation, endothelial dysfunction, and changes in vascular permeability in the brains of T2DM mice ( Nuthikattu et al, 2024 ). In T2DM patients, the NLRP3 inflammasome is significantly higher than in normal individuals, posing a risk for secondary cognitive impairment.…”

Section: Ceramide Mediated the Pathogenesis Of T2dm Combined With Admentioning

confidence: 99%

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Pan,

Li,

Lin

et al. 2024

Front. Pharmacol.

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The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance in vivo, serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

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“…For example, in a study by Yoo et al [355], diabetes-prone Zucker rats showed significantly greater hippocampal BBB permeability and significantly reduced expression of occludin and claudin-5 compared with nondiabetic control rats. In addition, using the mutant db/db mouse model of T2D, Nuthikattu et al [356] performed transcriptomic analyses in diabetic hippocampal endothelial cells and gadolinium contrast enhanced MRI to assess BBB permeability in the whole brain and the hippocampus. Compared to wildtype controls, the transcriptome of the diabetic mice revealed a pattern of gene expression changes in hippocampal endothelial cells that were indicative of dysfunction (e.g., disruption of cell-cell adhesion; disordered formation of tight junctions).…”

Section: Diabetesmentioning

confidence: 99%

Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction

Davidson,

Stevenson

2024

IJMS

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The hippocampus is a critical brain substrate for learning and memory; events that harm the hippocampus can seriously impair mental and behavioral functioning. Hippocampal pathophysiologies have been identified as potential causes and effects of a remarkably diverse array of medical diseases, psychological disorders, and environmental sources of damage. It may be that the hippocampus is more vulnerable than other brain areas to insults that are related to these conditions. One purpose of this review is to assess the vulnerability of the hippocampus to the most prevalent types of insults in multiple biomedical domains (i.e., neuroactive pathogens, neurotoxins, neurological conditions, trauma, aging, neurodegenerative disease, acquired brain injury, mental health conditions, endocrine disorders, developmental disabilities, nutrition) and to evaluate whether these insults affect the hippocampus first and more prominently compared to other brain loci. A second purpose is to consider the role of hippocampal blood–brain barrier (BBB) breakdown in either causing or worsening the harmful effects of each insult. Recent research suggests that the hippocampal BBB is more fragile compared to other brain areas and may also be more prone to the disruption of the transport mechanisms that act to maintain the internal milieu. Moreover, a compromised BBB could be a factor that is common to many different types of insults. Our analysis indicates that the hippocampus is more vulnerable to insults compared to other parts of the brain, and that developing interventions that protect the hippocampal BBB may help to prevent or ameliorate the harmful effects of many insults on memory and cognition.

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Single nuclei transcriptomics in diabetic mice reveals altered brain hippocampal endothelial cell function, permeability, and behavior

Cited by 7 publications

References 94 publications

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

Potential Intersections between lncRNA, Vascular Cognitive Impairment, and Immunization Strategies: Insights and Future Directions

A review of the mechanisms of abnormal ceramide metabolism in type 2 diabetes mellitus, Alzheimer’s disease, and their co-morbidities

Vulnerability of the Hippocampus to Insults: Links to Blood–Brain Barrier Dysfunction

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