Do Specialized Glycoproteins Prop Up Blood-Brain Barrier?

The blood-brain barrier weakens during normal aging and in neurodegenerative disease, but the reasons are not fully understood. In the February 26 Nature, scientists led by Tony Wyss-Coray and Carolyn Bertozzi at Stanford University, California, venture a suggestion. In mice, they found that mucin-domain glycoproteins, components of the carbohydrate meshwork that lines the interior of brain blood vessels, wane with age. In young mice, thinning out these sugary, bottlebrush-shaped proteins made brain blood vessels leak. Conversely, promoting glycosylation of the proteins in old mice firmed up the blood-brain barrier. This even helped prevent memory slippage.

  • In mice, mucin-domain glycoproteins on blood vessels wane with age.
  • Boosting their abundance in old mice firmed up the blood-brain barrier.
  • These glycoproteins also ebb in Alzheimer’s and Huntington’s disease.

The findings may be relevant to neurodegeneration. The authors detected a scarcity of mucin-domain glycoproteins in blood vessels from postmortem Alzheimer’s and Huntington’s brains. This could contribute to leaky blood vessels in those disorders, they suggested. Wyss-Coray considers glycosylation to be understudied in general. “We believe there is a vast trove of molecular information to be discovered by unlocking the patterns of glycosylation on molecules and cells,” he wrote to Alzforum.

Other scientists were impressed. “This is a paradigm-shifting publication for the blood-brain barrier field,” Tom Davis at the University of Arizona, Tucson, wrote to Alzforum. Justin Rustenhoven and Taylor Stevenson at the University of Auckland, New Zealand, found the result compelling. “The contribution of mucin-domain glycoproteins to blood-brain barrier stability is a novel and significant finding,” they wrote. Jacob Raber at Oregon Health and Science University, Portland, called the study data-rich, with potential for therapy development (comments below).

In related news, another recent paper investigated how the blood-cerebrospinal fluid barrier changes with age. There, senescent cells stimulated macrophages in the choroid plexus to secrete cathepsin S, breaking down tight junctions and causing leakage (related news to come).

Bottlebrush Barrier. The glycocalyx layer (purple, left) that coats brain blood vessels consists of numerous glycoproteins, glycolipids, and proteoglycans (right), including the bottlebrush-shaped mucin-domain glycoproteins (far right). [Courtesy of Shi et al., Nature.]

Brain blood vessels are coated with a thick, sugary layer known as the glycocalyx. Made up of proteoglycans, glycoproteins, and glycolipids, this meshwork helps protect endothelial cells. It modulates how well blood cells stick to vessel walls and communicate with endothelial cells, and it regulates transport of molecules through the vessel wall. Scientists believe the glycocalyx contributes to the blood-brain barrier, but little is known about how this works (Kutuzov et al., 2018; Ando et al., 2018).

Because the blood-brain barrier weakens with age, first author Sophia Shi compared the glycocalyx in 3-month-old and 21-month-old wild-type mice. In the old mice, this layer was about half as thick. Some think this might be an artifact of the preparation of older blood vessels. Still, RNA-Seq analysis found that the most suppressed genes in old endothelial cells were the enzymes that add sugars to mucin-domain glycoproteins. Mucin domains consist of repeating sequences rich in serines, threonines, and prolines, and are found on many proteins. Enzymes attach sugar chains to these residues, a process known as O-glycosylation. As a result of these dense side chains, mucin-domain glycoproteins develop a “bottlebrush” structure (image above).

The age-related drop in O-glycosylation enzymes should thin out these bottlebrushes. Confirming this, Shi and colleagues found about half as many mucin glycoproteins in brain blood vessels of old mice compared with young. Mass spectrometry showed this was not due to any change in the abundance of the glycoproteins. Instead, levels of the O-glycan enzymes C1GALT1 and B3GNT3 were about 66 percent and 75 percent, respectively, of that in young vessels. The abundance of each enzyme correlated with the amount of mucin-domain glycoproteins decorating the vessel walls.

Leaky Pipes. When mucin-domain glycoproteins were thinned out in brain blood vessels of mice (right), an intravenously injected dye (gold) penetrated into the cortex, whereas in controls it stayed put (left). [Courtesy of Shi et al., Nature.]

What happens when mucin-domain glycoproteins dwindle? The authors knocked down C1GALT1 in brain endothelial cells of 3-month-old mice using an adenovirus. Eight weeks later, mucin-domain glycoproteins were as sparse as they are in old mice. Notably, the blood-brain barrier became leaky, allowing an intravenously injected dye to penetrate the cortex (image above). When the authors instead injected a mucinase to directly chew up mucin glycoproteins, the effects were more dramatic. With 24 hours of exposure, brain blood vessels began to leak, and with 48 hours, they hemorrhaged, allowing red blood cells to infiltrate the brain (images below).

Poking Holes. In young mice, the thick glycocalyx layer (left) becomes skimpy (middle) after mucinase injection. This leads to hemorrhages, with red blood cells escaping vessels (right). [Courtesy of Shi et al., Nature.]

Exactly how mucin glycoproteins keep the barrier tight is unclear; however, the authors noted that after mucinase injection, there were about half as many intact tight junctions as before, and about 50 percent more reactive oxygen species (image below). Jonathan Kipnis and Leon Smyth at Washington University, St. Louis, speculated that the negatively charged glycocalyx may help shield endothelial cells from interactions with immune cells and cytokines, which are also negatively charged (comment below). Rustenhoven and Stevenson wondered whether the drop in mucin-domain glycoproteins contributes to peripheral immune cells infiltrating the aging brain.

Loose Junctions? Normally, tight junctions in brain blood vessels form an unbroken seal (white asterisks), but after 24 hours of mucinase treatment, gaps develop (red arrow) or detach entirely (red asterisk). [Courtesy of Shi et al., Nature.]

Boosting O-glycosylation had the opposite effect. The authors overexpressed C1GALT1 or B3GNT3 in brain endothelial cells of 17-month-old mice, again using an adenovirus. Eight weeks later, mucin glycoproteins had doubled, and the blood-brain barrier had become as tight as it is in young mice. Curiously, overexpression of B3GNT3, but not C1GALT1, maintained mouse memory in fear conditioning and Y-maze tests. Single-nuclei RNA-Seq of cortex showed that B3GNT3 expression pushed gene expression in neurons and glia back toward more youthful profiles. In particular, B3GNT3 cooled microglial inflammatory activation. Raber noted that these findings hint that neuroinflammation, rather than blood-brain barrier integrity per se, may drive age-related cognitive decline when the glycocalyx weakens.

Does neurodegenerative disease have similar effects to aging on mucin-domain glycoproteins? Leaky and damaged blood-brain barriers have been found in AD, HD, Parkinson’s, and other neurodegenerative diseases (Feb 2015 webinar; Sep 2015 news; Al-Bachari et al., 2020). The authors analyzed existing snRNA-Seq datasets from AD and HD brains, and found a consistent drop in eight O-glycan biosynthetic enzymes (Yang et al., 2022; Garcia et al., 2022). Supporting this, staining of vessels from postmortem AD brain detected about two-thirds as many mucin-domain glycoproteins as in age-matched controls.

Alzheimer's Thinning. Blood vessels from AD brain (bottom) express less CIGALT1 (red) and mucin-domain glycoprotein(purple) than vessels from healthy controls (top). [Courtesy of Shi et al., Nature.]

In future work, the authors will further explore how glycosylation in the glycocalyx changes with age and disease in different brain regions. They also want to identify the underlying proteins that serve as scaffolds for mucin-type O-glycosylation in the glycocalyx.

Commenters agreed the findings point toward new therapeutic strategies. “The ability to target the glycocalyx with viral vectors suggests that this work could be translated, either through viral vectors or drugs that target the enzymes that form the glycocalyx, to restore BBB function during aging or neurological disease,” Kipnis and Smyth wrote.—Madolyn Bowman Rogers

Comments

    • User Profile Image Tom Davis
      University of Arizona College of Medicine and Pharmacy
    • Posted:

    This is an outstanding manuscript. In the blood-brain barrier field, we now appreciate that the BBB is under constant “attack” by neurodegenerative disease states. Across most CNS diseases, it is now recognized that loss or dysregulation of BBB integrity at the level of the tight junction proteins, such as claudin 5, occludin, zona occludens-1, leads it to “leak.” That these authors demonstrate loss of BBB integrity, and then reverse that loss via restored and improved BBB integrity, is very exciting and a watershed publication for the BBB field.

    In the paper, the authors write that, “In addition to contributing to the structural integrity of the glycocalyx layer, mucin-domain glycoproteins have diverse biological roles, including in signaling, cell–cell interactions and regulation of membrane morphology.” This demonstrates their deep understanding of the BBB, a series of tight-knit endothelial cells with a unique, very high electrical resistance. The glycocalyx is much more than just an ultrastructural element. It signals, interacts, and regulates BBB morphology.

    I fully agree with the authors when they write “removal of mucin-domain glycoproteins from brain endothelial cells broadly compromises BBB integrity, including by modulating tight junctions, increasing oxidative stress, and disrupting other crucial vascular homeostatic pathways.” I also agree with this statement: “These results demonstrate that restoring the brain endothelial glycocalyx may be an effective therapeutic route to combat BBB breakdown in age-related CNS diseases.” I base my opinion on 45 years of much-appreciated NIH funding for our research on the BBB in stroke, pain, AD, hypoxia and drugs of abuse challenges.

    View all comments by Tom Davis

  2. This study offers compelling insight into the role of mucin-domain glycoproteins in the glycocalyx—a dense layer that coats the luminal surface of endothelial cells and serves as a critical interface between the bloodstream and the vasculature. Composed of glycoproteins, proteoglycans, and glycolipids, the glycocalyx provides mechanical stability, regulates vascular permeability, and modulates immune interactions at the blood-brain barrier. Shi et al. provide evidence that brain endothelial glycocalyx dysregulation is a central feature of aging and neurodegenerative disease.

    Their findings suggest that loss of mucin-type O-glycosylation contributes to BBB dysfunction and leakiness, key characteristics of neurodegenerative diseases such as Alzheimer's and Huntington’s, and that restoring these modifications can improve both vascular and cognitive function in aged mice. Importantly, taking advantage of previously published single cell-RNA sequencing datasets, they further revealed that key enzymes involved in mucin-type O-glycosylation are disrupted in Alzheimer's and Huntington's patients, highlighting the translational relevance of these findings.

    Using a combination of mucin-selective proteomics, in vivo glycocalyx degradation, and endothelial-specific genetic manipulations, the authors demonstrated that loss of mucin-domain glycoproteins compromises the BBB, allowing blood-derived factors to infiltrate the brain. This disruption was associated with oxidative stress, tight junction instability, and increased neuroinflammation, key contributors to neurodegeneration. Notably, AAV-mediated overexpression of the glycosyltransferases C1GALT1 and B3GNT3—key enzymes in mucin-type O-glycan biosynthesis—restored core mucin-type O-glycosylation. This restoration ultimately rescued BBB function, reduced microglial activation, and improved cognitive performance in aged mice. These findings open up possibilities for therapeutic strategies targeting the BBB glycocalyx for central nervous system rejuvenation in aging and age-related neurological diseases.

    While therapeutic restoration of mucin-domains in aging was beneficial in promoting vascular repair and associated neurological improvements, the specific mechanisms through which this is achieved remain unclear. This study raises questions about the broader role of glycosylation in neurodegeneration. While glycosaminoglycans like heparan sulfate have been widely studied, the contribution of mucin-domain glycoproteins to BBB stability is a novel and significant finding. It would be particularly interesting in this context to explore whether the reduced glycocalyx during aging contributes to elevated peripheral immune cell infiltration observed in the aged brain and whether this contributes to the observed BBB leakage, neuroinflammation, and cognitive decline—particularly given the group’s (and others’) prior work on T cell infiltration in the aged, and diseased, brain. It would also be interesting to explore additional factors that could contribute to mucin-type O-glycosylation disturbances beyond the reduction in glycosyltransferases, particularly whether various mucinases or proteases could be implicated in the age-related loss.

    The vascular heterogeneity observed in this study is particularly intriguing, as the authors report pronounced BBB dysfunction in the ventricles and brain borders such as the meninges, suggesting that certain regions of the vasculature may be more vulnerable to disruption. Notably, the study observed no similar reduction in luminal mucin-domain glycoprotein coverage in the heart or liver with aging, implying that the mechanisms altering BBB and brain border vascular function may be unique to the brain’s vasculature—a factor that could be highly advantageous for targeted therapies.

    However, it remains unclear why some areas of the brain’s vasculature and border regions are more affected than others. Further studies are needed to determine whether differences in endothelial composition, local immune environment, or regional metabolic demands contribute to this selective vulnerability. Understanding these mechanisms could provide crucial insight into how the glycocalyx functions across different segments of the brain’s vasculature, and identify specific pathways that drive age-related BBB dysfunction.

    Interestingly, no drugs have been found that specifically target components of the glycocalyx. This remains an intriguing avenue for therapeutic development. Given the challenges associated with gene therapy for humans, such as delivery and long-term expression, exploring small molecules or biologics that could modulate the glycocalyx or its key components may offer a less-invasive alternative for treating age-related BBB dysfunction and neurodegenerative diseases. Interventions aimed at restoring the glycocalyx could represent a promising new strategy for mitigating BBB breakdown in aging and disease.

    In conclusion, this study opens exciting possibilities for therapeutic intervention targeting the glycocalyx in neurodegenerative diseases. Future investigation into the underlying mechanisms involved will be crucial for determining whether these findings can be translated into effective treatments for aging-related vascular dysfunction and cognitive decline.

    View all comments by Justin Rustenhoven View all comments by Taylor Stevenson

  3. In this impressive and data-rich study, Shi et al. assessed the role of dysregulation of the endothelial glycocalyx in the function of the blood-brain-barrier in aging and neurodegenerative conditions. They revealed that, in wild-type mice, perturbation in O-glycosylated proteins (mucin-domain glycoproteins) results in dysregulation of the BBB and, in severe cases, in brain hemorrhaging. In addition, restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses (AAV-B3GNT3 and AAV-C1GALT1) improved BBB function and reduced neuroinflammation.

    However, treatment of 17-month-old mice for eight weeks with AAV-B3GNT3, but not with AAV-C1GALT1, improved hippocampus-dependent cognitive performance in the Y maze (percent spontaneous alternation) and hippocampus-dependent contextual fear memory, but not hippocampus-independent cued fear memory, in aged wild-type mice, as compared to age-matched AAV-EGFP controls. While similar beneficial effects of AAV-B3GNT3 and AAV-C1GALT1 were seen on all BBB-related markers, quantification of the area occupied by immunoreactivity of IBA1, a microglial marker, in the cortex was lower in AAV-B3GNT3-, but not in AAV-C1GALT1-treated mice, as compared to age-matched AAV-EGFP controls. These data suggest that neuroinflammation in combination with BBB injury might be driving cognitive injury, and that improving BBB function by itself might not be sufficient to improve cognitive function.

    The authors also conducted differential glycosylation-related gene analysis on previously published single-nucleus RNA-Seq (snRNA-Seq) datasets of Alzheimer’s and Huntington’s diseases; brain endothelial mucin-type O-glycan biosynthesis was revealed as a shared downregulated pathway enriched in both neurodegenerative conditions and was affected in the aged wild-type mice in this study as well, suggesting the potential for treating healthy age-related cognitive decline in the absence of frank dementia as well as for treating neurodegenerative conditions with dementia.

    An important role of the integrity of the BBB for cognitive health is consistent with studies in human apolipoprotein E3 and E4 targeted replacement mice on a standard and Western diet (Rhea et al., 2020; Rhea et al., 2021) and with the ability of viruses, including the non-replicating SARS-CoV-2 and viral proteins like the S1 protein of SARS-CoV-2, to cross the BBB and negatively affect brain function in mice (Rhea et al., 2020; Erickson et al., 2023; Raber et al., 2023). The results of the current study are also consistent with the decline in BBB function in aging and neurodegeneration (Andjelkovica et al., 2023) and efforts to protect or restore BBB function (Knox et al., 2022). The age-related changes in BBB function are more profound in individuals with E4 (Banks et al., 2021). 

    The upregulation of genes involved in heparan sulfate metabolism in brain endothelial cells reported in this study is consistent with the role of heparan sulfate in neuronal loss in fly models of AD (Schultheis et al., 2024) and the altered expression of heparan sulfate and its role in metabolism of Aβ in Alzheimer’s disease (Ozsan et al., 2023). 

    The upregulation of hyaluronan in isolated microvessels of aged mice as compared to the young wild-type mice is consistent with the positive correlation of HA with neuropathology in Alzheimer’s disease (Reed et al., 2019) and the association of age-related accumulation of HA in the hippocampus with reduced neurogenesis and cognitive injury (Su et al., 2017) 

    To assess the molecular changes in brain endothelial cells induced by mucin degradation, the authors performed bulk RNA-Seq on bEnd.3 cells after 16h of StcE treatment. Differential gene expression analysis revealed downregulation of genes involved in vascular development and integrity, TGF signaling, and in the regulation of reactive oxygen species, including the glutathione peroxidase 1 gene. These results are consistent with the role of ROS in aging and neurodegeneration and the recovery of spatial memory and reduced neuronal loss in the hippocampus following traumatic cortical brain injury to the developing brain in mice with transgenic overexpression of glutathione peroxidase  (Tsuru-Aoyagi et al., 2009). 

    For the mouse studies, young (3-month-old) and aged (17- to 19-month-old) wild-type mice were used. It would be good to consider including middle-aged mice in follow-up studies, as age-related brain changes in wild-type often start at middle age (Benice et al., 2006). Also, the age-related changes in hippocampus-dependent cognition (Benice et al., 2006) and in BBB function (Dion-Albert et al., 2022) are sex-dependent. Therefore, it will be important to compare these outcome measures in female and male mice (in the current study, it was not clear to me whether female and/or male mice were used). Also, it would be good to include wild-type mice without viral EGFP expression to exclude potential effects of EGFP on any of the outcome measures.

    It is very encouraging that the age-related dysregulation of the endothelial glycocalyx in BBB function seen in wild-type mice resembles that seen in patients with Alzheimer’s and Huntington’s. It will be important to consider follow-up studies using mouse models of Alzheimer’s, Huntington’s, and other neurodegenerative conditions.

    View all comments by Jacob Raber

  4. The microenvironment of the brain is controlled by a series of border tissues that regulate the entry and exit of molecules from the periphery. Chief amongst these is the blood-brain barrier (BBB), which refers to a series of properties in the brain endothelium: tight junctions, suppressed bulk transcytosis, and a range of import and efflux pumps. Less well-studied is the glycocalyx of the brain vasculature, which is very thick compared to the endothelial glycocalyx of other organs and forms a non-adhesive coating to blood vessels (Ando et al., 2018). 

    Here, Shi et al. show that the glycocalyx of the brain vasculature is dramatically altered in aging mice. It loses much of its coating, and changes composition. Most notably, a particular modification, mucin-type O-glycosylation, was found to be reduced. Further work suggested that this was related to changes in the glycosylation biosynthetic pathway, driven by C1galt1, an enzyme that adds glycans to mucins.

    Using an adenovirus under a promoter specific to endothelial cells (Cldn5) to target the BBB, Shi et al. then perturbed C1galt1 in mice. When its expression was reduced, there was dramatic BBB opening, and even the presence of bleeds. On the other hand, in old mice, rescue of another glycocalyx-modifying enzyme, B3gnt3, functionally restored BBB integrity and was sufficient to rescue cognitive dysfunction.

    This work sheds light on an understudied player in BBB biology, and there are many questions. What drives changes in the glycocalyx during aging and diseases? This could be triggered by brain dysfunction or circulating challenges, and indeed the glycocalyx is highly sensitive to inflammation (Ando et al., 2018). 

    Most importantly, how does the glycocalyx help maintain the BBB? The negatively charged glycocalyx may protect brain endothelial cells from the actions of circulating cytokines, which are predominantly negatively charged (Messina et al., 2024). Alternatively, the glycocalyx is a major impediment that restricts the interactions of immune cells with the BBB, so its loss may enable circulating immune cells to interact with the BBB, to trigger its breakdown (Schmidt et al., 2012). This may, in turn, contribute to capillary stalling as has been reported previously in mouse models of Alzheimer’s disease (Cruz Hernandez et al., 2019). 

    Finally, the ability to target the glycocalyx with viral vectors suggests that this work could be translated, either through viral vectors or drugs that target the enzymes that form the glycocalyx, to restore BBB function during aging or neurological disease.

    References:

    Ando Y, Okada H, Takemura G, Suzuki K, Takada C, Tomita H, Zaikokuji R, Hotta Y, Miyazaki N, Yano H, Muraki I, Kuroda A, Fukuda H, Kawasaki Y, Okamoto H, Kawaguchi T, Watanabe T, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Ogura S. Brain-Specific Ultrastructure of Capillary Endothelial Glycocalyx and Its Possible Contribution for Blood Brain Barrier. Sci Rep. 2018 Nov 30;8(1):17523. PubMed.

    Cruz Hernández JC, Bracko O, Kersbergen CJ, Muse V, Haft-Javaherian M, Berg M, Park L, Vinarcsik LK, Ivasyk I, Rivera DA, Kang Y, Cortes-Canteli M, Peyrounette M, Doyeux V, Smith A, Zhou J, Otte G, Beverly JD, Davenport E, Davit Y, Lin CP, Strickland S, Iadecola C, Lorthois S, Nishimura N, Schaffer CB. Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer's disease mouse models. Nat Neurosci. 2019 Mar;22(3):413-420. Epub 2019 Feb 11 PubMed.

    Messina JM, Luo M, Hossan MS, Gadelrab HA, Yang X, John A, Wilmore JR, Luo J. Unveiling cytokine charge disparity as a potential mechanism for immune regulation. Cytokine Growth Factor Rev. 2024 Jun;77:1-14. Epub 2023 Dec 26 PubMed.

    Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, Smith LP, Cheng SS, Overdier KH, Thompson KR, Geraci MW, Douglas IS, Pearse DB, Tuder RM. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med. 2012 Aug;18(8):1217-23. Epub 2012 Jul 22 PubMed.

    View all comments by Leon Smyth View all comments by Jonathan Kipnis

  5. This manuscript provides a comprehensive picture of changes in glycoprotein in the blood-brain barrier, offering an impressive view of the glycoprotein landscape along the lifespan of the mouse. The discovery that mucin-domain glycoproteins are lost during aging is critical in developing therapeutics for a large number of neurodegenerative diseases or even for normal, aging-mediated breakdown of the BBB. While this manuscript focuses more on the physical barrier glycoproteins provide for endothelial cells in the BBB, their role in signaling with other cellular components, including astrocytes and pericytes, but also even with neurons, will be highly important future directions of study that could reveal ways to delay or reverse neurodegeneration.

    View all comments by In-Hyun Park

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References

Webinar Citations

  1. Leaky Blood-Brain Barrier a Harbinger of Alzheimer's?

News Citations

  1. Barriers Between Blood and CSF, Brain Yield to Aβ—Not a Bad Thing?

Paper Citations

  1. Kutuzov N, Flyvbjerg H, Lauritzen M. Contributions of the glycocalyx, endothelium, and extravascular compartment to the blood-brain barrier. Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9429-E9438. Epub 2018 Sep 14 PubMed.
  2. Ando Y, Okada H, Takemura G, Suzuki K, Takada C, Tomita H, Zaikokuji R, Hotta Y, Miyazaki N, Yano H, Muraki I, Kuroda A, Fukuda H, Kawasaki Y, Okamoto H, Kawaguchi T, Watanabe T, Doi T, Yoshida T, Ushikoshi H, Yoshida S, Ogura S. Brain-Specific Ultrastructure of Capillary Endothelial Glycocalyx and Its Possible Contribution for Blood Brain Barrier. Sci Rep. 2018 Nov 30;8(1):17523. PubMed.
  3. Al-Bachari S, Naish JH, Parker GJ, Emsley HC, Parkes LM. Blood-Brain Barrier Leakage Is Increased in Parkinson's Disease. Front Physiol. 2020;11:593026. Epub 2020 Dec 22 PubMed.
  4. Yang AC, Vest RT, Kern F, Lee DP, Agam M, Maat CA, Losada PM, Chen MB, Schaum N, Khoury N, Toland A, Calcuttawala K, Shin H, Pálovics R, Shin A, Wang EY, Luo J, Gate D, Schulz-Schaeffer WJ, Chu P, Siegenthaler JA, McNerney MW, Keller A, Wyss-Coray T. A human brain vascular atlas reveals diverse mediators of Alzheimer's risk. Nature. 2022 Mar;603(7903):885-892. Epub 2022 Feb 14 PubMed.
  5. Garcia FJ, Sun N, Lee H, Godlewski B, Mathys H, Galani K, Zhou B, Jiang X, Ng AP, Mantero J, Tsai LH, Bennett DA, Sahin M, Kellis M, Heiman M. Single-cell dissection of the human brain vasculature. Nature. 2022 Mar;603(7903):893-899. Epub 2022 Feb 14 PubMed.

Further Reading

Primary Papers

  1. Shi SM, Suh RJ, Shon DJ, Garcia FJ, Buff JK, Atkins M, Li L, Lu N, Sun B, Luo J, To NS, Cheung TH, McNerney MW, Heiman M, Bertozzi CR, Wyss-Coray T. Glycocalyx dysregulation impairs blood-brain barrier in ageing and disease. Nature. 2025 Feb 26; Epub 2025 Feb 26 PubMed.

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