We are thrilled to announce our participation in a groundbreaking study in collaboration with Mayo Clinic, now published in Nature Communications. This research looks into the intricate role of blood-brain barrier disruptions in Alzheimer’s disease, leveraging the remarkable capabilities of zebrafish models in combination with vast antemortem and postmortem human brain datasets.
The blood-brain barrier is a critical checkpoint that protects our brain from harmful substances, but its breakdown is increasingly linked to the progression of Alzheimer’s. Our study provides fresh insights into how these disruptions can lead to neurodegeneration, offering potential new targets for therapeutic intervention.
Key highlights
- Blood-brain-barrier dysfunction: We explored how changes in the blood-brain barrier contribute to the onset and progression of Alzheimer’s disease. This barrier acts as a gatekeeper, ensuring that harmful substances do not enter the brain. Our findings suggest that when this barrier is compromised, it can lead to significant brain pathology.
- Zebrafish models: Utilizing advanced zebrafish models, known for their transparency and genetic similarity to humans, we were able to observe real-time changes in the brain’s vascular system. These models helped us pinpoint specific molecular mechanisms that may underlie blood-brain barrier disruptions in Alzheimer’s.
- Molecular insights: The research identified several key molecules involved in maintaining the integrity of the blood-brain barrier. Disruptions in these molecules were linked to the accumulation of toxic proteins in the brain, a hallmark of Alzheimer’s.
The findings from our study open new avenues for therapeutic strategies aimed at protecting or restoring the blood-brain barrier. By targeting the molecular pathways that we have identified, it may be possible to develop treatments that prevent or slow the progression of Alzheimer’s, ultimately improving the quality of life for millions affected by this devastating condition.
We invite you to read more about our exciting journey and findings in the full article available on Nature Communications: Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood-brain barrier dysfunction.
Congratulations to all authors!
Expert Blurb
In a recent collaborative effort with Mayo Clinic, our team has contributed to a pivotal study investigating the molecular dynamics of blood-brain barrier (BBB) dysfunction in Alzheimer’s disease (AD). This study, published in Nature Communications, employed single-nucleus RNA sequencing (snRNA-seq) to examine the transcriptomic landscape of the gliovascular unit (GVU), focusing on key cell types such as astrocytes and vascular cells in the temporal cortex of post-mortem AD and control brains.
Major Findings:
- SMAD3-VEGFA axis: We discovered significant upregulation of SMAD3 in pericytes and downregulation of VEGFA in astrocytes within AD brains. This disruption in the SMAD3–VEGFA signaling pathway is implicated in BBB dysfunction, contributing to neuroinflammation and impaired vascular function in AD.
- Pericyte and astrocyte interactions: Our analysis prioritized SMAD3 as a key molecular target, given its extensive interaction with astrocytic ligands like VEGFA. These findings were validated across multiple datasets and experimental models, including zebrafish, where we observed a conserved regulatory mechanism between VEGFA and SMAD3 impacting BBB integrity.
- Cross-species validation: In zebrafish models, downregulation of vegfaa (the zebrafish ortholog of VEGFA) in astrocytes and corresponding upregulation of smad3 in pericytes following amyloid-beta treatment underscored the relevance of these molecular changes in a model system, supporting their role in BBB pathology in AD.
- Human validation: Our study included validation of pericytic SMAD3 and astrocytic VEGFA expression in human brain tissue using RNAscope and immunohistochemistry, further substantiating the transcriptional changes observed in AD. Increased SMAD3 phosphorylation in AD pericytes was notably associated with impaired BBB function.
- Potential therapeutic targets: The identification of the SMAD3–VEGFA interaction opens new avenues for targeting these molecules to restore BBB function and mitigate neurodegenerative processes in AD. Our findings highlight the importance of focusing on vascular-astrocytic interactions to develop novel therapeutic strategies aimed at maintaining BBB integrity in neurodegenerative diseases.
This study exemplifies the power of interdisciplinary collaboration in elucidating complex disease mechanisms. By combining advanced transcriptomic techniques with robust validation across species, we have uncovered critical molecular pathways that may offer new targets for therapeutic intervention in Alzheimer’s disease. Our work underscores the potential of targeting gliovascular interactions to maintain BBB integrity and combat the progression of neurodegenerative diseases.
For more detailed information, please refer to our publication in Nature Communications: Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction.
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