Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues
Open accessPublished version of a preprint
Abstract
Brain endothelial cells (BECs) are key constituents of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access of circulatory factors. Yet, because circulatory proteins have prominent age-related effects on adult neurogenesis, neuroinflammation, and cognitive function in mice, we wondered whether BECs receive and potentially relay signals between the blood and brain. Using single-cell RNA sequencing of hippocampal BECs, we discover that capillary BECs-compared with arterial and venous BECs-undergo the greatest transcriptional changes in normal aging, upregulating innate immunity and oxidative stress response pathways. Short-term infusions of aged plasma into young mice recapitulate key aspects of this aging transcriptome, and remarkably, infusions of young plasma into aged mice exert rejuvenation effects on the capillary transcriptome. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Aging-related cell states exhibited upregulation of genes (e.g., B2m and Trem2 in Micro-3, Xdh in Endo-3, Gfap and C4b in Astro-2) previously shown to be enriched in activated microglia, endothelial cells, and astrocytes.
“These aging-related cell states exhibit upregulation of genes (e.g., B2m and Trem2 in Micro-3, Xdh in Endo-3, and Gfap and C4b in Astro-2) (Figure 2C) that have been previously shown to be enriched in microglia, endothelial cells, and astrocytes activated by inflammation and/or aging.”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [30]
The Results section, “Vessel Segments Exhibit Divergent Aging Transcriptomic Signatures” (page unavailable), reports B2m upregulation in aged brain endothelial cells and after inflammatory LPS treatment. Our copy does not establish the cited association of Xdh with activated endothelial cells or the stated microglial and astrocytic gene associations; the Micro-3, Endo-3, and Astro-2 states are identified by the citing paper’s own Figure 2C. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPrevious transcriptomic studies have revealed widespread changes in cell state in specific cell types with age, with many highlighting increased inflammation as a key aspect of brain aging.
“Previous transcriptomic studies have revealed widespread changes in cell state in specific cell types with age, with many of these studies highlighting a role for increased inflammation as a key aspect of brain aging.17–20,25–30”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [30]
The number of samples for the single-cell sequencing studies was set using prior studies and preliminary experiments that confirmed sufficient BECs would be available for statistical analysis.
“To determine the samples size for the single-cell sequencing studies, we used previous studies13,26 and performed preliminary studies to confirm that we will obtain enough BECs for statistical analysis (not included in the manuscript).”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [13]
Single-cell RNAseq studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as a function of the transcriptome.
“Indeed, single cell RNAseq studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as a function of the transcriptome.70”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [70]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · cited 1× · see citing works
“While the cell-intrinsic hallmarks of aging, from stem cell exhaustion to loss of proteostasis, are established aspects of brain aging (López-Otín et al., 2013), recent studies have demonstrated cell non-autonomous mechanisms of brain aging via heterochronic parabiosis or blood plasma infusions (Wyss-Coray, 2016).”
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · cited 2× · see citing works
“Next, the Canonical Correlation Analysis function from the Seurat package (Butler et al., 2018) was used to align raw data from multiple experiments, data from aged versus young mice, AMP versus YMP treated young mice, and LPS treated versus untreated mice.”
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595 · cited 15× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
InfluentialMitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388 · cited 1× · see citing works
“Increases in reactive oxygen species (ROS) have been consistently observed in aging and accumulation of oxidative damage to macromolecules is a hallmark of aging, contributing to cellular senescence, loss of proliferation, and secretion of chemokines, interleukins and MMPs (Balaban et al., 2005; Liguori et al., 2018).”
Full-length RNA-seq from single cells using Smart-seq2
Picelli, S., Faridani, O. R., Björklund, Å. K., Winberg, G., Sagasser, S., & Sandberg, R. (2014) · Nature Protocols · doi:10.1038/nprot.2014.006 · Cited by 4,137 · cited 2× · see citing works
“Single cell RNA-sequencing—Cell lysis, first-strand synthesis and cDNA synthesis was performed using the Smart-seq-2 protocol as described previously (Picelli et al., 2014) in both 96-well and 384-well formats, with some modifications.”
Oxidative stress, aging, and diseases
Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., Gargiulo, G., Testa, G., Cacciatore, F., Bonaduce, D., et al. (2018) · Clinical Interventions in Aging · doi:10.2147/cia.s158513 · Cited by 3,979 · cited 1× · see citing works
“Increases in reactive oxygen species (ROS) have been consistently observed in aging and accumulation of oxidative damage to macromolecules is a hallmark of aging, contributing to cellular senescence, loss of proliferation, and secretion of chemokines, interleukins and MMPs (Balaban et al., 2005; Liguori et al., 2018).”
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459 · cited 1× · see citing works
“, Stmn2, Prnp, Nos3, Sod1, Apoe, Vwf, Alpl, Ctsd, Alpl2, App Sqstm1, and Clstn1) and brain aging (Cuyvers et al., 2015; Dahiyat et al., 1999; Guerreiro et al., 2014; Liu et al., 2013; Vardy et al., 2012; Wolters et al., 2018), highlighting the potential for BECs to contribute to molecular mechanisms and functional def…”
Daneman, R., & Prat, A. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020412 · Cited by 3,437 · cited 15× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
InfluentialSingle-cell transcriptomics of 20 mouse organs creates a Tabula Muris
The Tabula Muris Consortium, coordination, O., coordination, L., processing, O. C. A., sequencing, L. P. A., analysis, C. D., annotation, C. T., Writing group, Supplemental text writing group, & Principal investigators (2018) · Nature · doi:10.1038/s41586-018-0590-4 · Cited by 3,326 · see citing works
The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
Zlokovic, B. V. (2008) · Neuron · doi:10.1016/j.neuron.2008.01.003 · Cited by 3,280 · cited 2× · see citing works
“Dysfunction and breakdown of this unit have been implicated in age-related neurodegeneration and manifest in reduced cerebral blood flow, leakage of toxic factors, and a general inability to maintain an optimal environment for neuronal and stem cell function (Bell et al., 2012; Iadecola, 2013; Sweeney et al., 2018; Zh…”
Pericytes regulate the blood–brain barrier
Armulik, A., Genové, G., Mäe, M., Nisancioglu, M. H., Wallgard, E., Niaudet, C., He, L., Norlin, J., Lindblom, P., Strittmatter, K., et al. (2010) · Nature · doi:10.1038/nature09522 · Cited by 2,843 · cited 1× · see citing works
“These special properties are induced in development and maintained in adulthood by surrounding pericytes, smooth muscle cells, astrocytes, and neurons that form a functional “neurovascular unit” (Armulik et al., 2010; Daneman et al., 2010).”
FINE STRUCTURAL LOCALIZATION OF A BLOOD-BRAIN BARRIER TO EXOGENOUS PEROXIDASE
Reese, T. S., & Karnovsky, M. J. (1967) · The Journal of Cell Biology · doi:10.1083/jcb.34.1.207 · Cited by 2,629 · cited 15× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
InfluentialGenomic atlas of the human plasma proteome
Sun, B. B., Maranville, J. C., Peters, J. E., Stacey, D., Staley, J. R., Blackshaw, J., Burgess, S., Jiang, T., Paige, E., Surendran, P., et al. (2018) · Nature · doi:10.1038/s41586-018-0175-2 · Cited by 2,268 · cited 1× · see citing works
“These ligands have also been reported to increase in human plasma with age (Sun et al., 2018; Tanaka et al., 2018).”
Kimura, K. D., Tissenbaum, H. A., Liu, Y., & Ruvkun, G. (1997) · Science · doi:10.1126/science.277.5328.942 · Cited by 2,250 · cited 1× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
Pericytes are required for blood–brain barrier integrity during embryogenesis
Daneman, R., Zhou, L., Kebede, A. A., & Barres, B. A. (2010) · Nature · doi:10.1038/nature09513 · Cited by 2,128 · cited 1× · see citing works
“These special properties are induced in development and maintained in adulthood by surrounding pericytes, smooth muscle cells, astrocytes, and neurons that form a functional “neurovascular unit” (Armulik et al., 2010; Daneman et al., 2010).”
Blood-brain barrier breakdown in the aging human hippocampus
Montagne, A., Barnes, S. R., Sweeney, M. D., Halliday, M. R., Sagare, A. P., Zhao, Z., Toga, A. W., Jacobs, R. E., Liu, C. Y., Amezcua, L., et al. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.032 · Cited by 2,102 · see citing works
A molecular atlas of cell types and zonation in the brain vasculature
Vanlandewijck, M., He, L., Mäe, M. A., Andrae, J., Ando, K., Del Gaudio, F., Nahar, K., Lebouvier, T., Laviña, B., Gouveia, L., et al. (2018) · Nature · doi:10.1038/nature25739 · Cited by 2,074 · cited 8× · see citing works
“Vcam1, a cell surface receptor that facilities endothelialimmune cell interactions, has previously been shown to be highly enriched in arterial and venous cells (Vanlandewijck et al., 2018; Yousef et al., 2019).”
InfluentialThe Pathobiology of Vascular Dementia
Iadecola, C. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.008 · Cited by 1,857 · cited 2× · see citing works
“Dysfunction and breakdown of this unit have been implicated in age-related neurodegeneration and manifest in reduced cerebral blood flow, leakage of toxic factors, and a general inability to maintain an optimal environment for neuronal and stem cell function (Bell et al., 2012; Iadecola, 2013; Sweeney et al., 2018; Zh…”
The ageing systemic milieu negatively regulates neurogenesis and cognitive function
Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., et al. (2011) · Nature · doi:10.1038/nature10357 · Cited by 1,763 · see citing works
Self-citationPhenotypic Heterogeneity of the Endothelium
Aird, W. C. (2007) · Circulation Research · doi:10.1161/01.res.0000255691.76142.4a · Cited by 1,744 · see citing works
Establishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670 · cited 1× · see citing works
“Dysfunction and breakdown of this unit have been implicated in age-related neurodegeneration and manifest in reduced cerebral blood flow, leakage of toxic factors, and a general inability to maintain an optimal environment for neuronal and stem cell function (Bell et al., 2012; Iadecola, 2013; Sweeney et al., 2018; Zh…”
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Tatar, M., Kopelman, A. H., Epstein, D., Tu, M., Yin, C. ‐., & Garofalo, R. S. (2001) · Science · doi:10.1126/science.1057987 · Cited by 1,630 · cited 1× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
Disruption of Large-Scale Brain Systems in Advanced Aging
Andrews-Hanna, J. R., Snyder, A. Z., Vincent, J. L., Lustig, C., Head, D., Raichle, M. E., & Buckner, R. L. (2007) · Neuron · doi:10.1016/j.neuron.2007.10.038 · Cited by 1,592 · cited 1× · see citing works
“Aging drives the deterioration of brain structure and function, increasing susceptibility to neurodegenerative disease and cognitive decline (Andrews-Hanna et al., 2007; Bishop et al., 2010; Mattson and Magnus, 2006).”
RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., et al. (2003) · Nature Medicine · doi:10.1038/nm890 · Cited by 1,426 · cited 1× · see citing works
“Well-established endothelial receptors including Lrp1 and Ager (receptor for advanced glycation endproducts [RAGE]) (Deane et al., 2003; Storck et al., 2016) were confirmed to be present in capillary segments.”
Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323 · cited 1× · see citing works
“Aging drives the deterioration of brain structure and function, increasing susceptibility to neurodegenerative disease and cognitive decline (Andrews-Hanna et al., 2007; Bishop et al., 2010; Mattson and Magnus, 2006).”
Apolipoprotein E controls cerebrovascular integrity via cyclophilin A
Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., Holtzman, D. M., Betsholtz, C., Armulik, A., Sallstrom, J., et al. (2012) · Nature · doi:10.1038/nature11087 · Cited by 1,293 · cited 1× · see citing works
“Dysfunction and breakdown of this unit have been implicated in age-related neurodegeneration and manifest in reduced cerebral blood flow, leakage of toxic factors, and a general inability to maintain an optimal environment for neuronal and stem cell function (Bell et al., 2012; Iadecola, 2013; Sweeney et al., 2018; Zh…”
The blood-brain barrier in systemic inflammation
Varatharaj, A., & Galea, I. (2017) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2016.03.010 · Cited by 1,172 · see citing works
Ageing, neurodegeneration and brain rejuvenation
Wyss-Coray, T. (2016) · Nature · doi:10.1038/nature20411 · Cited by 1,147 · cited 5× · see citing works
“…M anuscript Luminal Exposure of BECs to Young Plasma Reverses Aspects of Transcriptional Aging The plasma of young mice can rejuvenate the brains of aged mice, as assessed by enhanced neurogenesis, memory and learning, dendritic spine density, and diminished neuroinflammation (Wyss-Coray, 2016).”
InfluentialSelf-citationYoung blood reverses age-related impairments in cognitive function and synaptic plasticity in mice
Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., et al. (2014) · Nature Medicine · doi:10.1038/nm.3569 · Cited by 1,081 · cited 1× · see citing works
“Immunofluorescence tissue staining—Brain tissue processing and immunofluorescence experiments were performed as described previously (Castellano et al., 2017; Villeda et al., 2014).”
Self-citationAgeing and neuronal vulnerability
Mattson, M. P., & Magnus, T. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn1886 · Cited by 1,075 · cited 1× · see citing works
“Aging drives the deterioration of brain structure and function, increasing susceptibility to neurodegenerative disease and cognitive decline (Andrews-Hanna et al., 2007; Bishop et al., 2010; Mattson and Magnus, 2006).”
Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid
Nguyen, L. N., Ma, D., Shui, G., Wong, P., Cazenave-Gassiot, A., Zhang, X., Wenk, M. R., Goh, E. L. K., & Silver, D. L. (2014) · Nature · doi:10.1038/nature13241 · Cited by 1,048 · cited 1× · see citing works
“MFSD2A is critical for the formation of the BBB by limiting non-specific caveolar transcytosis (Andreone et al., 2017; Ben-Zvi et al., 2014; Nguyen et al., 2014).”
Mfsd2a is critical for the formation and function of the blood-brain barrier
Ben-Zvi, A., Lacoste, B., Kur, E., Andreone, B. J., Mayshar, Y., Yan, H., & Gu, C. (2014) · Nature · doi:10.1038/nature13324 · Cited by 1,037 · cited 2× · see citing works
“Relative to peripheral endothelium, the BBB exhibits limited permeability to macromolecules by employing unique tight junctions and low rates of transcytosis (Andreone et al., 2017; Ben-Zvi et al., 2014; Chow and Gu, 2015).”
Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors
Katsimpardi, L., Litterman, N. K., Schein, P. A., Miller, C. M., Loffredo, F. S., Wojtkiewicz, G. R., Chen, J. W., Lee, R. T., Wagers, A. J., & Rubin, L. L. (2014) · Science · doi:10.1126/science.1251141 · Cited by 1,037 · cited 2× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
The role of brain vasculature in neurodegenerative disorders
Sweeney, M. D., Kisler, K., Montagne, A., Toga, A. W., & Zlokovic, B. V. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0234-x · Cited by 998 · cited 1× · see citing works
“Dysfunction and breakdown of this unit have been implicated in age-related neurodegeneration and manifest in reduced cerebral blood flow, leakage of toxic factors, and a general inability to maintain an optimal environment for neuronal and stem cell function (Bell et al., 2012; Iadecola, 2013; Sweeney et al., 2018; Zh…”
Undulating changes in human plasma proteome profiles across the lifespan
Lehallier, B., Gate, D., Schaum, N., Nanasi, T., Lee, S. E., Yousef, H., Moran Losada, P., Berdnik, D., Keller, A., Verghese, J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0673-2 · Cited by 981 · cited 2× · see citing works
“Interestingly, we identified Bmpr2 (ligands: BMP7 and GDF9), Flt4 (ligand: FN1), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), and Lsr (ligand: APOB) not only as genes upregulated in both aging and AMP exposure, but also whose ligands significantly increase in the plasma of aged mice (Lehallier et al.…”
Self-citationEpigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · cited 1× · see citing works
“Whether this emerging hallmark of aging and its modulation have functional consequences will be the focus of future work (Pal and Tyler, 2016; Sen et al., 2016).”
Loffredo, F. S., Steinhauser, M. L., Jay, S. M., Gannon, J., Pancoast, J. R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J. L., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.015 · Cited by 948 · cited 1× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
A draft network of ligand–receptor-mediated multicellular signalling in human
Ramilowski, J. A., Goldberg, T., Harshbarger, J., Kloppmann, E., Lizio, M., Satagopam, V. P., Itoh, M., Kawaji, H., Carninci, P., Rost, B., et al. (2015) · Nature Communications · doi:10.1038/ncomms8866 · Cited by 887 · cited 2× · see citing works
“We then matched the resulting 15 BEC external membrane proteins with putative plasma ligands using a published database of receptor-ligand pairs (Ramilowski et al., 2015), highlighting the ligands we detected in mouse plasma.”
Brain Imaging in Alzheimer Disease
Johnson, K. A., Fox, N. C., Sperling, R. A., & Klunk, W. E. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006213 · Cited by 875 · cited 1× · see citing works
“The hippocampus appears particularly vulnerable to aging, exhibiting the first signs of degeneration in Alzheimer’s disease (Bobinski et al., 2000; Johnson et al., 2012; Pennanen et al., 2004).”
Pal, S., & Tyler, J. K. (2016) · Science Advances · doi:10.1126/sciadv.1600584 · Cited by 860 · cited 1× · see citing works
“Whether this emerging hallmark of aging and its modulation have functional consequences will be the focus of future work (Pal and Tyler, 2016; Sen et al., 2016).”
Wnt/β-catenin signaling controls development of the blood–brain barrier
Liebner, S., Corada, M., Bangsow, T., Babbage, J. W., Taddei, A., Czupalla, C. J., Reis, M., Felici, A., Wolburg, H., Fruttiger, M., et al. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200806024 · Cited by 831 · cited 1× · see citing works
“Wnt/ β-catenin signaling is necessary for maintaining specialized BBB properties, such as tight junction expression and low expression of leukocyte adhesion molecules, but is compromised upon injury, inflammation, and likely during aging (Lengfeld et al., 2017; Liebner et al., 2008; Tran et al., 2015; Zhou and Nathans…”
Nitric oxide and oxidative stress in vascular disease
Förstermann, U. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0808-2 · Cited by 780 · cited 2× · see citing works
“…al., 2004), and endothelial nitric oxide synthase (eNOS) traffic inducer (Nostrin), an endothelial-specific attenuator of vascular oxidative stress (Förstermann, 2010), are upregulated with aging and AMP infusions, possibly reflecting a protective response induced by factors present in aged plasma.”
Single-cell transcriptomic profiling of the aging mouse brain
Ximerakis, M., Lipnick, S. L., Innes, B. T., Simmons, S. K., Adiconis, X., Dionne, D., Mayweather, B. A., Nguyen, L., Niziolek, Z., Ozek, C., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0491-3 · Cited by 736 · cited 1× · see citing works
“Consistent with a recent report (Ximerakis et al., 2019), we also find a consistent upregulation of ribosomal subunit genes across vessel segments (e.”
Hippocampus and entorhinal cortex in mild cognitive impairment and early AD
Pennanen, C., Kivipelto, M., Tuomainen, S., Hartikainen, P. H., Hänninen, T., Laakso, M. P., Hallikainen, M., Vanhanen, M., Nissinen, A. M., Helkala, E., et al. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00084-8 · Cited by 646 · cited 2× · see citing works
“The hippocampus appears particularly vulnerable to aging, exhibiting the first signs of degeneration in Alzheimer’s disease (Bobinski et al., 2000; Johnson et al., 2012; Pennanen et al., 2004).”
Banks, W. A., Gray, A. M., Erickson, M. A., Salameh, T. S., Damodarasamy, M., Sheibani, N., Meabon, J. S., Wing, E. E., Morofuji, Y., Cook, D. G., et al. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0434-1 · Cited by 636 · see citing works
Andreone, B. J., Chow, B. W., Tata, A., Lacoste, B., Ben-Zvi, A., Bullock, K., Deik, A. A., Ginty, D. D., Clish, C. B., & Gu, C. (2017) · Neuron · doi:10.1016/j.neuron.2017.03.043 · Cited by 636 · cited 2× · see citing works
“Relative to peripheral endothelium, the BBB exhibits limited permeability to macromolecules by employing unique tight junctions and low rates of transcytosis (Andreone et al., 2017; Ben-Zvi et al., 2014; Chow and Gu, 2015).”
Aging-induced type I interferon response at the choroid plexus negatively affects brain function
Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., et al. (2014) · Science · doi:10.1126/science.1252945 · Cited by 615 · cited 1× · see citing works
“Several of these genes, such as Ifnar1, have been reported to promote the deleterious effects of brain aging via IFN signaling (Baruch et al., 2014).”
Self-citationPlasma proteomic signature of age in healthy humans
Tanaka, T., Biancotto, A., Moaddel, R., Moore, A. Z., Gonzalez‐Freire, M., Aon, M. A., Candia, J., Zhang, P., Cheung, F., Fantoni, G., et al. (2018) · Aging Cell · doi:10.1111/acel.12799 · Cited by 562 · see citing works
β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis
Smith, L. K., He, Y., Park, J.-S., Bieri, G., Snethlage, C. E., Lin, K., Gontier, G., Wabl, R., Plambeck, K. E., Udeochu, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3898 · Cited by 500 · cited 3× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript have recapitulated the effects of plasma, such as the pro-aging B2M and CCL11, and the rejuvenating tissue inhibitor of metalloproteinases 2 (TIMP2) (Castellano et al., 2017; Smith et al., 2015; Villeda et al., 2011).”
Self-citationEndothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier
Storck, S. E., Meister, S., Nahrath, J., Meißner, J. N., Schubert, N., Di Spiezio, A., Baches, S., Vandenbroucke, R. E., Bouter, Y., Prikulis, I., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81108 · Cited by 477 · see citing works
ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration
Zhong, Z., Deane, R., Ali, Z., Parisi, M., Shapovalov, Y., O'Banion, M. K., Stojanovic, K., Sagare, A., Boillee, S., Cleveland, D. W., et al. (2008) · Nature Neuroscience · doi:10.1038/nn2073 · Cited by 476 · see citing works
Bobinski, M., de Leon, M. J., Wegiel, J., DeSanti, S., Convit, A., Saint Louis, L. A., Rusinek, H., & Wisniewski✠, H. M. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00476-5 · Cited by 455 · cited 1× · see citing works
“The hippocampus appears particularly vulnerable to aging, exhibiting the first signs of degeneration in Alzheimer’s disease (Bobinski et al., 2000; Johnson et al., 2012; Pennanen et al., 2004).”
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., et al. (2017) · Nature · doi:10.1038/nature22067 · Cited by 445 · cited 4× · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript have recapitulated the effects of plasma, such as the pro-aging B2M and CCL11, and the rejuvenating tissue inhibitor of metalloproteinases 2 (TIMP2) (Castellano et al., 2017; Smith et al., 2015; Villeda et al., 2011).”
InfluentialSelf-citationYousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0440-4 · Cited by 442 · cited 9× · see citing works
“Vcam1, a cell surface receptor that facilities endothelialimmune cell interactions, has previously been shown to be highly enriched in arterial and venous cells (Vanlandewijck et al., 2018; Yousef et al., 2019).”
InfluentialSelf-citationAmyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer's disease
Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., & Mucke, L. (1997) · Nature · doi:10.1038/39321 · Cited by 417 · cited 1× · see citing works
“Of note, TGF-β signaling in the vasculature has been linked to age-related basement membrane thickening and cerebral amyloid angiopathy (Wyss-Coray et al., 1997) and to inhibition of neural progenitor cell proliferation in the hippocampus (Buckwalter et al.”
Self-citationA panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease
Carrette, O., Demalte, I., Scherl, A., Yalkinoglu, O., Corthals, G. L., Burkhard, P. R., Hochstrasser, D. F., & Sanchez, J. (2003) · PROTEOMICS · doi:10.1002/pmic.200300470 · Cited by 375 · cited 1× · see citing works
“Suggestive of a functional role, plasma B2m increases in human patients with HIV-associated dementia and Alzheimer’s disease (Carrette et al., 2003); and infusions exert negative effects on hippocampal neurogenesis and cognition in mice (Smith et al.”
The Molecular Constituents of the Blood–Brain Barrier
Chow, B. W., & Gu, C. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.08.003 · Cited by 374 · cited 1× · see citing works
“Relative to peripheral endothelium, the BBB exhibits limited permeability to macromolecules by employing unique tight junctions and low rates of transcytosis (Andreone et al., 2017; Ben-Zvi et al., 2014; Chow and Gu, 2015).”
Hu, Z., Chen, K., Xia, Z., Chavez-Tomar, M., Pal, S., Seol, J.-H., Chen, C., Li, W., & Tyler, J. K. (2014) · Genes & Development · doi:10.1101/gad.233221.113 · Cited by 330 · cited 1× · see citing works
“The majority of DEGs were increased (86%) rather than decreased, suggesting a general up-regulation of transcriptional programs (Figure 3C), corroborating recent reports (Hu et al., 2014; Zhao et al., 2019).”
Impact of apoE genotype on oxidative stress, inflammation and disease risk
Jofre‐Monseny, L., Minihane, A. M., & Rimbach, G. H. (2008) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200700322 · Cited by 319 · see citing works
Gpr158 mediates osteocalcin’s regulation of cognition
Khrimian, L., Obri, A., Ramos-Brossier, M., Rousseaud, A., Moriceau, S., Nicot, A.-S., Mera, P., Kosmidis, S., Karnavas, T., Saudou, F., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171320 · Cited by 308 · cited 1× · see citing works
“Specifically, old plasma impairs, and young plasma revitalizes, cognitive function and hippocampal neurogenesis (Castellano et al., 2017; Katsimpardi et al., 2014; Khrimian et al., 2017; Villeda et al., 2011, 2014; Yousef et al., 2019).”
Age-Dependent Niche Signals from the Choroid Plexus Regulate Adult Neural Stem Cells
Silva-Vargas, V., Maldonado-Soto, A. R., Mizrak, D., Codega, P., & Doetsch, F. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.06.013 · Cited by 306 · cited 1× · see citing works
“An aged circulatory environment can promote brain dysfunction (Silva-Vargas et al., 2016; Villeda et al., 2011; Yousef et al., 2019).”
Effect of aging on the blood-brain barrier
Mooradian, A. D. (1988) · Neurobiology of Aging · doi:10.1016/s0197-4580(88)80013-7 · Cited by 296 · cited 2× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies
Zuchero, Y. J. Y., Chen, X., Bien‐Ly, N., Bumbaca, D., Tong, R. K., Gao, X., Zhang, S., Hoyte, K., Luk, W., Huntley, M. A., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.11.024 · Cited by 283 · see citing works
Serra, V., von Zglinicki, T., Lorenz, M., & Saretzki, G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m207939200 · Cited by 278 · cited 1× · see citing works
“Interestingly, transcript levels of superoxide dismutase (Sod1)–an antioxidant shown to increase lifespan, decrease the rate of telomere shortening (Serra et al., 2003), protect AD model mice (Murakami et al.”
Blood–brain-barriers in aging and in Alzheimer’s disease
Marques, F., Sousa, J. C., Sousa, N., & Palha, J. A. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-38 · Cited by 273 · cited 1× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
Zhou, Y., & Nathans, J. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.08.018 · Cited by 265 · cited 1× · see citing works
“Wnt/ β-catenin signaling is necessary for maintaining specialized BBB properties, such as tight junction expression and low expression of leukocyte adhesion molecules, but is compromised upon injury, inflammation, and likely during aging (Lengfeld et al., 2017; Liebner et al., 2008; Tran et al., 2015; Zhou and Nathans…”
Heterogeneity of the blood-brain barrier
Wilhelm, I., Nyúl‐Tóth, Á., Suciu, M., Hermenean, A. O., & Krizbai, I. A. (2016) · Tissue Barriers · doi:10.1080/21688370.2016.1143544 · Cited by 246 · see citing works
Murakami, K., Murata, N., Noda, Y., Tahara, S., Kaneko, T., Kinoshita, N., Hatsuta, H., Murayama, S., Barnham, K. J., Irie, K., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.279208 · Cited by 241 · cited 1× · see citing works
“, 2003), protect AD model mice (Murakami et al., 2011), and maintain BBB function (Zhong et al.”
Tran, K. A., Zhang, X., Predescu, D., Huang, X., Machado, R. F., Göthert, J. R., Malik, A. B., Valyi-Nagy, T., & Zhao, Y.-Y. (2016) · Circulation · doi:10.1161/circulationaha.115.015982 · Cited by 219 · see citing works
Lack of Widespread BBB Disruption in Alzheimer’s Disease Models: Focus on Therapeutic Antibodies
Bien-Ly, N., Boswell, C. A., Jeet, S., Beach, T. G., Hoyte, K., Luk, W., Shihadeh, V., Ulufatu, S., Foreman, O., Lu, Y., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.036 · Cited by 198 · cited 1× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
Broadwell, R. D. (1989) · Acta Neuropathologica · doi:10.1007/bf00294368 · Cited by 172 · cited 15× · see citing works
“Indeed, while age-related BBB dysfunction has been probed with a diverse toolkit of tracers (Bien-Ly et al., 2015; Marques et al., 2013; Montagne et al., 2015; Mooradian, 1988), the transcriptional response of vessel segment-specific BECs to aging and changes in the systemic environment have not yet been explored in-d…”
InfluentialEndothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis
Lengfeld, J. E., Lutz, S. E., Smith, J. R., Diaconu, C., Scott, C., Kofman, S. B., Choi, C., Walsh, C. M., Raine, C. S., Agalliu, I., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609905114 · Cited by 152 · cited 1× · see citing works
“Wnt/ β-catenin signaling is necessary for maintaining specialized BBB properties, such as tight junction expression and low expression of leukocyte adhesion molecules, but is compromised upon injury, inflammation, and likely during aging (Lengfeld et al., 2017; Liebner et al., 2008; Tran et al., 2015; Zhou and Nathans…”
Milman, S., Huffman, D. M., & Barzilai, N. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.014 · Cited by 150 · cited 1× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
Buckwalter, M. S., Yamane, M., Coleman, B. S., Ormerod, B. K., Chin, J. T., Palmer, T. D., & Wyss‐Coray, T. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.051272 · Cited by 141 · cited 1× · see citing works
“Of note, TGF-β signaling in the vasculature has been linked to age-related basement membrane thickening and cerebral amyloid angiopathy (Wyss-Coray et al., 1997) and to inhibition of neural progenitor cell proliferation in the hippocampus (Buckwalter et al., 2006; Yousef et al., 2015b).”
Self-citationZhao, L., Li, Z., Vong, J. S. L., Chen, X., Lai, H. M., Yan, L. Y. C., Huang, J., Sy, S. K. H., Tian, X. Y., Huang, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18249-3 · Cited by 119 · see citing works
Wang, Y., Sabbagh, M. F., Gu, X., Rattner, A., Williams, J., & Nathans, J. (2019) · eLife · doi:10.7554/elife.43257 · Cited by 116 · cited 1× · see citing works
“Recently, β-catenin expression alone has been found sufficient to convert leaky vessels in circumventricular organs to a barrier-type state, with stabilized junctions and decreased tracer permeability (Benz et al., 2019; Wang et al., 2019).”
Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L. J., Paliwal, P., Greer, C. D., Conboy, I. M., & Schaffer, D. V. (2015) · Oncotarget · doi:10.18632/oncotarget.3851 · Cited by 115 · cited 1× · see citing works
“, 1997) and to inhibition of neural progenitor cell proliferation in the hippocampus (Buckwalter et al., 2006; Yousef et al., 2015b).”
Self-citationLutz, S. E., Smith, J. R., Kim, D. H., Olson, C. V. L., Ellefsen, K. L., Bates, J. M., Gandhi, S., & Agalliu, D. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.094 · Cited by 114 · see citing works
Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis
Yousef, H., Morgenthaler, A., Schlesinger, C., Bugaj, L. J., Conboy, I. M., & Schaffer, D. V. (2014) · Stem Cells · doi:10.1002/stem.1943 · Cited by 109 · cited 3× · see citing works
“Standing out in this list are Bmpr2 (ligands: BMP7 and GDF9), Ifnar1 (ligand: IFNA10), Igf1r (ligands: CDH1, GPC3, and INS), all of which have been implicated in organismal longevity and brain aging and whose plasma ligands similarly change with age (Katsimpardi et al., 2014; Kimura et al., 1997; Loffredo et al., 2013…”
Self-citationAlkaline Phosphatase Is Increased in both Brain and Plasma in Alzheimer’s Disease
Vardy, E. R. L. C., Kellett, K. A. B., Cocklin, S. L., & Hooper, N. M. (2011) · Neurodegenerative Diseases · doi:10.1159/000329722 · Cited by 92 · cited 1× · see citing works
“, Stmn2, Prnp, Nos3, Sod1, Apoe, Vwf, Alpl, Ctsd, Alpl2, App Sqstm1, and Clstn1) and brain aging (Cuyvers et al., 2015; Dahiyat et al., 1999; Guerreiro et al., 2014; Liu et al., 2013; Vardy et al., 2012; Wolters et al., 2018), highlighting the potential for BECs to contribute to molecular mechanisms and functional def…”
Benz, F., Wichitnaowarat, V., Lehmann, M., Germano, R. F. V., Mihova, D., Macas, J., Adams, R. H., Taketo, M. M., Plate, K.-H., Guérit, S., et al. (2019) · eLife · doi:10.7554/elife.43818 · Cited by 85 · cited 1× · see citing works
“Recently, β-catenin expression alone has been found sufficient to convert leaky vessels in circumventricular organs to a barrier-type state, with stabilized junctions and decreased tracer permeability (Benz et al., 2019; Wang et al., 2019).”
Ramos, J. M. P., Iribarren, P., Bousset, L., Melki, R., Baekelandt, V., & der Perren, A. V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00080 · Cited by 54 · see citing works
Qiu, L., Qiao, T., Beers, M. A., Tan, W., Wang, H., Yang, B., & Xu, Z. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-1 · Cited by 53 · see citing works
Czupalla, C. J., Yousef, H., Wyss‐Coray, T., & Butcher, E. C. (2018) · BIO-PROTOCOL · doi:10.21769/bioprotoc.3092 · Cited by 50 · see citing works
Self-citationJeong, D.-W., Kim, E., Kim, T. S., Chung, Y. W., Kim, H., & Kim, I. Y. (2004) · Molecules and Cells · doi:10.1016/s1016-8478(23)13021-4 · Cited by 41 · cited 1× · see citing works
“Similarly, selenoprotein W (Selenow), an antioxidant that protects cells from peroxide-mediated damage (Jeong et al., 2004), and endothelial nitric oxide synthase (eNOS) traffic inducer (Nostrin), an endothelial-specific attenuator of vascular oxidative stress (Förstermann, 2010), are upregulated with aging and AMP in…”
Cuyvers, E., van der Zee, J., Bettens, K., Engelborghs, S., Vandenbulcke, M., Robberecht, C., Dillen, L., Merlin, C., Geerts, N., Graff, C., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.02.014 · Cited by 35 · see citing works
Wolters, F. J., Boender, J., de Vries, P. S., Sonneveld, M., Koudstaal, P. J., de Maat, M. P. M., Franco, O. H., Ikram, M. K., Leebeek, F. W. G., & Ikram, M. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-23865-7 · Cited by 34 · cited 1× · see citing works
“, Stmn2, Prnp, Nos3, Sod1, Apoe, Vwf, Alpl, Ctsd, Alpl2, App Sqstm1, and Clstn1) and brain aging (Cuyvers et al., 2015; Dahiyat et al., 1999; Guerreiro et al., 2014; Liu et al., 2013; Vardy et al., 2012; Wolters et al., 2018), highlighting the potential for BECs to contribute to molecular mechanisms and functional def…”
A nonsense mutation in PRNP associated with clinical Alzheimer's disease
Guerreiro, R. J., Brás, J., Wojtas, A., Rademakers, R., Hardy, J., & Graff-Radford, N. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.05.013 · Cited by 32 · cited 1× · see citing works
“…(e.g., Stmn2, Prnp, Nos3, Sod1, Apoe, Vwf, Alpl, Ctsd, Alpl2, App Sqstm1, and Clstn1) and brain aging (Cuyvers et al., 2015; Dahiyat et al., 1999; Guerreiro et al., 2014; Liu et al., 2013; Vardy et al., 2012; Wolters et al., 2018), highlighting the potential for BECs to contribute to molecular…”
Papain-based Single Cell Isolation of Primary Murine Brain Endothelial Cells Using Flow Cytometry
Yousef, H., Czupalla, C. J., Lee, D. P., Butcher, E. C., & Wyss‐Coray, T. (2018) · BIO-PROTOCOL · doi:10.21769/bioprotoc.3091 · Cited by 26 · cited 9× · see citing works
“While VCAM1 FACS enrichment boosted arterial/venous cell numbers and enhanced discretization of these segmental populations in unsupervised clustering, we sought to ensure this did not confound age-related DEGs by repeating the differential expression analysis with only BECs sorted in an unbiased manner (CD31+CD45−Cd1…”
InfluentialSelf-citationYousef, H., Czupalla, C. J., Lee, D. P., Burke, A., Chen, M., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/242198 · Cited by 9 · see citing works
Self-citationZonation-dependent single-endothelial cell transcriptomic changes in the aged brainPreprint
Zhao, L., Li, Z., Vong, J. S. L., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/800318 · Cited by 6 · cited 2× · see citing works
“The majority of DEGs were increased (86%) rather than decreased, suggesting a general up-regulation of transcriptional programs (Figure 3C), corroborating recent reports (Hu et al., 2014; Zhao et al., 2019).”
Langston, J. W., Forno, L. S., Tetrud, J., Reeves, A. G., Kaplan, J. A., & Karluk, D. (1999) · Annals of Neurology · doi:10.1002/1531-8249(199910)46:4 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk
Yang, A. C., Vest, R. T., Kern, F., Lee, D. P., Agam, M., Maat, C. A., Losada, P. M., Chen, M. B., Schaum, N., Khoury, N., et al. (2022) · Nature · doi:10.1038/s41586-021-04369-3 · Cited by 797 · see citing works
Self-citationRevisiting the neurovascular unit
Schaeffer, S. M., & Iadecola, C. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00904-7 · Cited by 655 · see citing works
Dysregulation of brain and choroid plexus cell types in severe COVID-19
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03710-0 · Cited by 620 · see citing works
Self-citationVascular endothelial cell development and diversity
Trimm, E., & Red-Horse, K. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00770-1 · Cited by 537 · see citing works
Immunomodulation by endothelial cells — partnering up with the immune system?
Amersfoort, J., Eelen, G., & Carmeliet, P. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00694-4 · Cited by 549 · see citing works
Capillary cell-type specialization in the alveolus
Gillich, A., Zhang, F., Farmer, C. G., Travaglini, K. J., Tan, S. Y., Gu, M., Zhou, B., Feinstein, J. A., Krasnow, M. A., & Metzger, R. J. (2020) · Nature · doi:10.1038/s41586-020-2822-7 · Cited by 490 · see citing works
Physiological blood–brain transport is impaired with age by a shift in transcytosis
Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2453-z · Cited by 477 · see citing works
Self-citationMolecular and spatial signatures of mouse brain aging at single-cell resolution
Allen, W. E., Blosser, T. R., Sullivan, Z. A., Dulac, C., & Zhuang, X. (2023) · Cell · doi:10.1016/j.cell.2022.12.010 · Cited by 423 · see citing works
“, B2m and Trem2 in Micro-3, Xdh in Endo-3, and Gfap and C4b in Astro-2) (Figure 2C) that have been previously shown to be enriched in microglia, endothelial cells, and astrocytes activated by inflammation and/or aging.(17,25,26,29,30,40) Consistent with T cell infiltration into the aging brain,(41) we also observed a…”
Exercise plasma boosts memory and dampens brain inflammation via clusterin
De Miguel, Z., Khoury, N., Betley, M. J., Lehallier, B., Willoughby, D., Olsson, N., Yang, A. C., Hahn, O., Lu, N., Vest, R. T., et al. (2021) · Nature · doi:10.1038/s41586-021-04183-x · Cited by 422 · see citing works
Self-citationCounteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span
Grunewald, M., Kumar, S., Sharife, H., Volinsky, E., Gileles‐Hillel, A., Licht, T., Permyakova, A., Hinden, L., Azar, S., Friedmann, Y., et al. (2021) · Science · doi:10.1126/science.abc8479 · Cited by 370 · see citing works
A systems view of the vascular endothelium in health and disease
Augustin, H. G., & Koh, G. Y. (2024) · Cell · doi:10.1016/j.cell.2024.07.012 · Cited by 370 · see citing works
A single-cell atlas of the normal and malformed human brain vasculature
Winkler, E. A., Kim, C. N., Ross, J. M., Garcia, J. H., Gil, E., Oh, I., Chen, L. Q., Wu, D., Catapano, J. S., Raygor, K. P., et al. (2022) · Science · doi:10.1126/science.abi7377 · Cited by 324 · see citing works
Identification of a choroid plexus vascular barrier closing during intestinal inflammation
Carloni, S., Bertocchi, A., Mancinelli, S., Bellini, M., Erreni, M., Borreca, A., Braga, D., Giugliano, S., Mozzarelli, A. M., Manganaro, D., et al. (2021) · Science · doi:10.1126/science.abc6108 · Cited by 272 · see citing works
Propson, N. E., Roy, E. R., Litvinchuk, A., Köhl, J., & Zheng, H. (2021) · Journal of Clinical Investigation · doi:10.1172/jci140966 · Cited by 258 · see citing works
Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration
Pluvinage, J. V., & Wyss-Coray, T. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0255-9 · Cited by 191 · see citing works
Self-citationSingle-cell atlas of the human brain vasculature across development, adulthood and disease
Wälchli, T., Ghobrial, M., Schwab, M., Takada, S., Zhong, H., Suntharalingham, S., Vetiska, S., Rodríguez, D. G., Wu, R., Rehrauer, H., et al. (2024) · Nature · doi:10.1038/s41586-024-07493-y · Cited by 199 · see citing works
Liu, C.-C., Zhao, J., Fu, Y., Inoue, Y., Ren, Y., Chen, Y., Doss, S. V., Shue, F., Jeevaratnam, S., Bastea, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01127-0 · Cited by 168 · see citing works
Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease
Sun, N., Akay, L. A., Murdock, M. H., Park, Y., Galiana-Melendez, F., Bubnys, A., Galani, K., Mathys, H., Jiang, X., Ng, A. P., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01334-3 · Cited by 175 · see citing works
“Moreover, regulators in the same tfModule frequently had related functions; for example, module M1 regulators had roles in vEndo cell function, growth and adhesion 22–30 .”
BackgroundWang, W., Tan, J., Nima, L., Sang, Y., Cai, X. D., & Xue, H. (2022) · Food Chemistry X · doi:10.1016/j.fochx.2022.100414 · Cited by 161 · see citing works
“In addition, polysaccharides from Auricularia auricula could be degraded into short-chain fatty acids to play its immunomodulatory role through activation the MAPK signal pathway, which promoted the production of proinflammatory cytokines and maturation of T/B lymphocytes (Chen et al., 2020a).”
BackgroundBlood-to-brain communication in aging and rejuvenation
Bieri, G., Schroer, A. B., & Villeda, S. A. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01238-8 · Cited by 156 · see citing works
Insights into Alzheimer’s disease from single-cell genomic approaches
Murdock, M. H., & Tsai, L.-H. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01222-2 · Cited by 148 · see citing works
Glycocalyx dysregulation impairs blood–brain barrier in ageing and disease
Shi, S. M., Suh, R. J., Shon, D. J., García, F., Buff, J. K., Atkins, M., Li, L., Lu, N., Sun, B., Luo, J., et al. (2025) · Nature · doi:10.1038/s41586-025-08589-9 · Cited by 160 · see citing works
Self-citationA circadian clock regulates efflux by the blood-brain barrier in mice and human cells
Zhang, S., Lahens, N. F., Yue, Z., Arnold, D. M., Pakstis, P. P., Schwarz, J. E., & Sehgal, A. (2021) · Nature Communications · doi:10.1038/s41467-020-20795-9 · Cited by 159 · see citing works
Zhao, L., Li, Z., Vong, J. S. L., Chen, X., Lai, H. M., Yan, L. Y. C., Huang, J., Sy, S. K. H., Tian, X. Y., Huang, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18249-3 · Cited by 119 · see citing works
Causes and consequences of baseline cerebral blood flow reductions in Alzheimer’s disease
Bracko, O., Hernández, J. C. C., Park, L., Nishimura, N., & Schaffer, C. B. (2021) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x20982383 · Cited by 122 · see citing works
The pathogenesis of cerebral small vessel disease and vascular cognitive impairment
Markus, H. S., & Joutel, A. (2025) · Physiological Reviews · doi:10.1152/physrev.00028.2024 · Cited by 130 · see citing works
Asynchronous, contagious and digital aging
Rando, T. A., & Wyss-Coray, T. (2021) · Nature Aging · doi:10.1038/s43587-020-00015-1 · Cited by 121 · see citing works
Self-citationWang, Y., Sabbagh, M. F., Gu, X., Rattner, A., Williams, J., & Nathans, J. (2019) · eLife · doi:10.7554/elife.43257 · Cited by 116 · see citing works
Sun, Z., Gao, C., Gao, D., Sun, R., Li, W., Wang, F., Wang, Y., Cao, H., Zhou, G., Zhang, J., et al. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00255-2 · Cited by 115 · see citing works
“It should be noted that although our findings suggest that a reduction in pericyte coverage leads to BBB dysfunction through increased endothelial transcytosis following CCH, it is not clear why EC, which represent a direct link between blood and neural function, are not the primary cause of BBB dysfunction [55].”
BackgroundSingle-cell transcriptomics reveals functionally specialized vascular endothelium in brain
Jeong, H., Diéguez‐Hurtado, R., Arf, H., Song, J., Park, H., Kruse, K., Sorokin, L. M., & Adams, R. H. (2022) · eLife · doi:10.7554/elife.57520 · Cited by 105 · see citing works
Schulz, J., Hartz, A. M. S., & Bauer, B. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000025 · Cited by 109 · see citing works
Ali, M., Falkenhain, K., Njiru, B. N., Murtaza-Ali, M., Ruiz‐Uribe, N. E., Haft‐Javaherian, M., Catchers, S., Nishimura, N., Schaffer, C. B., & Bracko, O. (2021) · Brain · doi:10.1093/brain/awab387 · Cited by 97 · see citing works
“77 This is supported by recent single-nucleus transcriptome analysis of endothelial cells, which have shown an increased level of genes involved in vascular inflammation in aged healthy humans 55 and patients with Alzheimer’s disease.”
The blood–brain barrier: a help and a hindrance
Rust, R., Yin, H. R., Buil, B. A., Sagare, A. P., & Kisler, K. (2025) · Brain · doi:10.1093/brain/awaf068 · Cited by 102 · see citing works
“30,149 Also, plasma proteomes originating from different organs in humans can estimate organ-specific ageing differences.”
The pathobiology of neurovascular aging
Santisteban, M. M., & Iadecola, C. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.014 · Cited by 92 · see citing works
Can exercise training teach us how to treat Alzheimer's disease?
Huuha, A. M., Norevik, C. S., Moreira, J. B. N., Kobro-Flatmoen, A., Scrimgeour, N., Kivipelto, M., Van Praag, H., Ziaei, M., Sando, S. B., Wisløff, U., et al. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101559 · Cited by 79 · see citing works
Ximerakis, M., Holton, K. M., Giadone, R. M., Ozek, C., Saxena, M., Santiago, S., Adiconis, X., Dionne, D. A., Nguyễn, L., Shah, K. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00373-6 · Cited by 82 · see citing works
“In the CNS specifically, studies from our lab 25,26 and others 24,27–30 have shown that circulating factors in young blood stimulate functional improvement in aged and diseased brains.”
InfluentialHuang, X., Wei, P., Fang, C., Yu, M., Yang, S., Qiu, L., Wang, Y., Xu, A., Hoo, R. L. C., & Chang, J. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03261-x · Cited by 81 · see citing works
“The staining result for Mfsd2a, a potent suppressor of tran-scytosis, showed that Mfsd2a was significantly reduced by LPS treatment compared to saline treatment in WT mice, in line with a previous report [64].”
ResultBrain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability
Cui, Y., Wang, Y., Song, X., Ning, H., Zhang, Y., Teng, Y., Wang, J., & Yang, X. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109327 · Cited by 75 · see citing works
Bryant, A. G., Li, Z., Jayakumar, R., Serrano‐Pozo, A., Woost, B., Hu, M., Woodbury, M. E., Wachter, A., Lin, G., Kwon, T., et al. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.0237-23.2023 · Cited by 78 · see citing works
Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health
Katusic, Z. S., d’Uscio, L. V., & He, T. (2023) · Stroke · doi:10.1161/strokeaha.122.041444 · Cited by 73 · see citing works
CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges
das Neves, S. P., Delivanoglou, N., & Mesquita, S. D. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.655052 · Cited by 70 · see citing works
Zhang, X., Wang, R., Chen, H., Jin, C., Jin, Z., Lü, J., Xu, L., Lu, Y., Zhang, J., & Shi, L. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00289-6 · Cited by 65 · see citing works
“Consistent with recent reports [14, 31, 33], we found an upregulation of immune/cytokine signaling (adaptive immune response, interferon signaling, and antigen presentation) and ribosome biogenesis for all vascular segments (Fig.”
ResultCellular senescence in Alzheimer’s disease: from physiology to pathology
Zhu, J., Wu, C., & Yang, L. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00447-4 · Cited by 70 · see citing works
Khoury, N., Pizzo, M. E., Discenza, C. B., Joy, D. A., Tatarakis, D., Todorov, M. I., Negwer, M., Ha, C., de Melo, G. L., Sarrafha, L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57108-x · Cited by 73 · see citing works
“To determine if ATVs are differentially taken up by BEC subtypes, we next subclustered BECs into arterial, capillary, and venous populations based on markers established in previous mouse single-cell studies 64,65 (Supplementary Fig.”
Effect of peripheral cellular senescence on brain aging and cognitive decline
Budamagunta, V., Kumar, A., Rani, A., Bean, L. A., Manohar‐Sindhu, S., Yang, Y., Zhou, D., & Foster, T. C. (2023) · Aging Cell · doi:10.1111/acel.13817 · Cited by 65 · see citing works
“Increased gene expression was observed for the transforming growth factor beta (TGFβ) receptor signaling pathway, consistent with an age- related BBB dysfunction (Chen et al., 2020; Senatorov Jr et al., 2019).”
BackgroundGarnett, C. N., Watson, J. B., Higgins, E. K., Quan, N., & Bachstetter, A. D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.688254 · Cited by 60 · see citing works
“leukocyte infiltration, and (8) astrocyte retraction from the barrier.”
BackgroundAcıoğlu, Ç., & Elkabes, S. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03360-3 · Cited by 64 · see citing works
Therapeutic and Diagnostic Potential of Exosomes as Drug Delivery Systems in Brain Cancer
Avgoulas, D. Ι., Tasioulis, K. S., Papi, R. M., & Pantazaki, Α. A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15051439 · Cited by 59 · see citing works
Jia, P., Peng, Q., Fan, X., Zhang, Y., Xu, H., Li, J., Sonita, H., Liu, S., Le, A. C. T., Hu, Q., et al. (2024) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14853 · Cited by 58 · see citing works
“BECs play a crucial role in maintaining CNS homeostasis by limit - ing the entry of circulating WBCs and blood molecules into the CNS. 19 Following ICH, peripheral immune cells infiltrate the sur - rounding tissues of the hematoma through the damaged BBB.”
BackgroundMicroglial Priming in Infections and Its Risk to Neurodegenerative Diseases
Lima, M. N., Barbosa‐Silva, M. C., & Maron‐Gutierrez, T. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.878987 · Cited by 57 · see citing works
“Aging is a risk factor for the development of many neurodegenerative diseases because the natural aging process includes functional and structural changes within the brain (Bennett et al., 1996; Reeve et al., 2014; Maniega et al., 2015; Chen et al., 2020).”
BackgroundSakamuri, S. S. V. P., Sure, V. N. L. R., Kolli, L., Evans, W. R., Sperling, J. A., Bix, G. J., Wang, X., Atochin, D. N., Murfee, W. L., Mostany, R., et al. (2022) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x211069266 · Cited by 55 · see citing works
Labarta-Bajo, L., & Allen, N. J. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.010 · Cited by 58 · see citing works
Ramos, J. M. P., Iribarren, P., Bousset, L., Melki, R., Baekelandt, V., & der Perren, A. V. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00080 · Cited by 54 · see citing works
A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
Yang, A. C., Vest, R. T., Kern, F., Lee, D. P., Maat, C. A., Losada, P. M., Chen, M. B., Agam, M., Schaum, N., Khoury, N., et al. (2021) · doi:10.1101/2021.04.26.441262 · Cited by 48 · see citing works
Self-citationDach1 Extends Artery Networks and Protects Against Cardiac Injury
Raftrey, B. C., Williams, I. M., Coronado, P. E. R., Fan, X., Chang, A. H., Zhao, M., Roth, R., Trimm, E., Racelis, R., D’Amato, G., et al. (2021) · Circulation Research · doi:10.1161/circresaha.120.318271 · Cited by 50 · see citing works
“This is consistent with previous analyses showing that brain and heart capillary ECs exist along a continuum of arterial-venous identity, even in adults (Chen et al., 2020; Su et al., 2018; Vanlandewijck et al., 2018).”
ResultCao, M. C., Cawston, E. E., Chen, G. L., Brooks, C., Douwes, J. E., McLean, D., Graham, E. S., Dragunow, M., & Scotter, E. L. (2022) · BMC Neurology · doi:10.1186/s12883-022-02730-1 · Cited by 47 · see citing works
Engineered 3D immuno-glial-neurovascular human miBrain model
Stanton, A. E., Bubnys, A., Agbas, E., James, B. T., Park, D. S., Jiang, A. Y. L., Pinals, R. L., Liu, L., Truong, N., Loon, A. R., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2511596122 · Cited by 46 · see citing works
CD36 – A novel molecular target in the neurovascular unit
Ioghen, O. C., Chiţoiu, L., Gherghiceanu, M., Ceafalan, L. C., & Hinescu, M. E. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15147 · Cited by 45 · see citing works
Next-generation in vitro blood–brain barrier models: benchmarking and improving model accuracy
Linville, R. M., & Searson, P. C. (2021) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00291-y · Cited by 43 · see citing works
“, mural cells) [31, 32], cylindrical geometry [33], blood composition [34, 35], and neuronal activity [36].”
BackgroundLi, Z., Chen, X., Vong, J. S. L., Zhao, L., Huang, J., Yan, L. Y. C., Ip, B., Wing, Y. K., Lai, H.-M., Mok, V. C. T., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02208-9 · Cited by 42 · see citing works
Bhatia, K., Ahmad, S., Kindelin, A., & Ducruet, A. F. (2021) · Journal of Clinical Investigation · doi:10.1172/jci144348 · Cited by 44 · see citing works
Markov, N. T., Lindbergh, C. A., Staffaroni, A. M., Pérez, K., Stevens, M., Nguyen, K., Murad, N. F., Fonseca, C. S., Campisi, J., Kramer, J. H., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2207181119 · Cited by 43 · see citing works
Receptor–mediated transcytosis of macromolecules across the blood–brain barrier
Baghirov, H. (2023) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2023.2255138 · Cited by 43 · see citing works
“…[45]; this misfor-tune has also befallen some commonly used RMT targets, none more so than low-density lipoprotein receptor-related protein 1 whose levels on BCEC are between negligible and undetectable in bulk RNAseq [46,47], scRNAseq [48,49], and proteomics of CD31+/CD45-FACS-isolated BCEC [36].”
MethodEstablished, New and Emerging Concepts in Brain Vascular Development
Gupta, A., Rarick, K. R., & Ramchandran, R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.636736 · Cited by 41 · see citing works
Barkaway, A., Attwell, D., & Korte, N. (2022) · Neurophotonics · doi:10.1117/1.nph.9.3.031914 · Cited by 37 · see citing works
“addition, the level of MFSD2a is reduced upon LPS exposure, suggesting its expression can be modulated by inflammation.(281) Interestingly, lymphocyte transcellular migration (migration”
BackgroundGulej, R., Nyúl‐Tóth, Á., Csík, B., Patai, R., Petersen, B., Negri, S., Chandragiri, S. S., Shanmugarama, S., Mukli, P., Yabluchanskiy, A., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01154-8 · Cited by 38 · see citing works
“…mechanisms in cerebromicrovascular aging and highlights potential targets for promoting cerebro-vascular health and cognitive function Vol.: (0123456789) rejuvenate the endothelium and improve neurovascular coupling responses, which are critical for the aged brain’s functionality [103, 110–112].”
Aging of the Vascular System and Neural Diseases
Watanabe, C., Imaizumi, T., Kawai, H., Suda, K., Honma, Y., Ichihashi, M., Ema, M., & Mizutani, K. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.557384 · Cited by 34 · see citing works
“A recent study showed that capillary endothelial cells (ECs) in the aged brain exhibit transcriptional change primarily, in comparison with arterial and venous cells (Chen et al., 2020).”
BackgroundDecoding Aging Hallmarks at the Single-Cell Level
Ma, S., Chi, X., Cai, Y., Ji, Z., Wang, S., Ren, J., & Liu, G. (2023) · Annual Review of Biomedical Data Science · doi:10.1146/annurev-biodatasci-020722-120642 · Cited by 37 · see citing works
Spatially resolved transcriptome of the aging mouse brain
Wu, C., Tu, T., Xie, M., Wang, Y., Yan, B., Gong, Y., Zhang, J., Zhou, X., & Xie, Z. (2024) · Aging Cell · doi:10.1111/acel.14109 · Cited by 32 · see citing works
“A previous study also showed that the innate immunity-related Ifi27 gene was upregulated in aging brain endothelial cells (Chen et al., 2020).”
BackgroundModelling Human Physiology on-Chip: Historical Perspectives and Future Directions
Pun, S., Haney, L. C., & Barrile, R. (2021) · Micromachines · doi:10.3390/mi12101250 · Cited by 33 · see citing works
Brain aging and rejuvenation at single-cell resolution
Sun, E., Nagvekar, R., Pogson, A. N., & Brunet, A. (2025) · Neuron · doi:10.1016/j.neuron.2024.12.007 · Cited by 33 · see citing works
“49 The increase in inflammation could be a consequence of the infiltration of immune cells such as T cells in the old brain (see the following section).”
Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration
Omar, O. M., Kimble, A. L., Ashok, C., Tyburski, J. D., Pandey, S., Wu, Q., Reese, B., Jellison, E. R., Hao, B., Li, Y., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01914-5 · Cited by 35 · see citing works
“Alterations in ECs remain poorly annotated across age and disease states in the human brain, although animal models suggest a prominent role in both vascular aging and neurodegenerative disease 4,34–36 .”
Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?
Rybtsova, N., Berezina, T. N., Kagansky, A., & Александрович, Р. С. (2020) · Biomedicines · doi:10.3390/biomedicines8120615 · Cited by 33 · see citing works
Circadian Mechanisms in Brain Fluid Biology
Vizcarra, V. S., Fame, R. M., & Hablitz, L. M. (2024) · Circulation Research · doi:10.1161/circresaha.123.323516 · Cited by 30 · see citing works
“209 When young mice receive blood factors from aged mice, there is decreased adult neurogenesis, 210,211 increased inflammatory states of microglia 212 and brain endothelial cells, 213 and cognitive functions, 210 further demonstrating blood-brain cross talk.”
BackgroundBlood–brain barrier dysfunction in aging is mediated by brain endothelial senescence
Novo, J. P., Gee, L. E., Caetano, C., Tomé, I., Vilaça, A., von Zglinicki, T., Moreira, I. S., Jurk, D., Rosa, S. C., & Ferreira, L. (2024) · Aging Cell · doi:10.1111/acel.14270 · Cited by 30 · see citing works
“For this purpose, we To further confirm the impact of senescence on the BBB in aged mice, we used single-cell RNA sequencing data from BECs isolated from aged mice (Figure S4) as previously reported (Chen et al., 2020; Ximerakis et al., 2019; Zhao et al., 2020).”
Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature
Bieri, G., Pratt, K. J. B., Fuseya, Y., Aghayev, T., Sucharov, J., Horowitz, A. M., Philp, A. R., Fonseca-Valencia, K., Chu, R., Phan, M., et al. (2026) · Cell · doi:10.1016/j.cell.2026.01.024 · Cited by 30 · see citing works
Self-citationAge-Related Alterations in Immune Function and Inflammation: Focus on Ischemic Stroke
Chen, Q., Wu, M., Tang, Q., Yan, P., & Zhu, L. (2023) · Aging and Disease · doi:10.14336/ad.2023.0721-1 · Cited by 33 · see citing works
“Additionally, short-term infusion of aged plasma into young mice upregulated innate immune and oxidative stress response pathways [40].”
BackgroundThe influence of physiological and pathological perturbations on blood-brain barrier function
Zhao, N., Chung, T. D., Guo, Z., Jamieson, J. J., Liang, L. R., Linville, R. M., Pessell, A. F., Wang, L., & Searson, P. C. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1289894 · Cited by 30 · see citing works
“Transcriptomic studies in mice have shown significant differences in aged mice compared to young mice, with upregulation of pathways associated with innate immunity and oxidative stress response (Chen M. B. et al., 2020).”
BackgroundGulej, R., Patai, R., Ungvari, A., Kállai, A., Tarantini, S., Yabluchanskiy, A., Huffman, D. M., Conboy, M. J., Conboy, I. M., Mika Kivimaki, B., et al. (2025) · GeroScience · doi:10.1007/s11357-025-01657-y · Cited by 29 · see citing works
Current and Future Treatments of Vascular Cognitive Impairment
Ip, B. Y. M., Ko, H., Lam, B. Y. K., Au, L. W. C., Lau, A. Y. L., Huang, J., Kwok, A. J., Leng, X., Cai, Y., Leung, T. W. H., et al. (2024) · Stroke · doi:10.1161/strokeaha.123.044174 · Cited by 26 · see citing works
Völgyi, K., González-Gallego, J., Müller, S. A., Beaufort, N., Malik, R., Schifferer, M., Todorov, M. I., Crusius, D., Robinson, S., Schmidt, A., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00598-z · Cited by 24 · see citing works
“…receptor-mediated transport to non-specific caveolar endocytosis 30 . scRNA-seq studies further revealed zonation-dependent transcriptomic changes in aged BECs 31,32 and an upregulation of innate immunity and oxidative stress response pathways in capillary BECs from old compared to young mice 31 .”
Body-wide multi-omic counteraction of aging with GLP-1R agonism
Huang, J., Kwok, A. J., Li, J. C. Y., Chiu, C. L. H., Ip, B. Y. M., Tung, L. Y., Chan, R. C. H., Chan, D. T.-M., Wang, Z., Zheng, X., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.10.014 · Cited by 31 · see citing works
Expanding the understanding of insulin resistance in brain and periphery
Chen, W., Kullmann, S., & Rhea, E. M. (2025) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2025.04.010 · Cited by 23 · see citing works
Self-citationPhysiological and Pathological Remodeling of Cerebral Microvessels
Tregub, P. P., Сергеевич, А. А., Baranich, T. I., Ryazanova, M. V., & Salmina, A. B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012683 · Cited by 23 · see citing works
The age-dependent immune response to ischemic stroke
Tuohy, M. C., Hillman, E. M. C., Marshall, R. S., & Agalliu, D. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102670 · Cited by 23 · see citing works
Shin, Y. J., Evitts, K. M., Jin, S., Howard, C. C., Sharp-Milgrom, M., Schwarze‐Taufiq, T. A., Kinoshita, C., Young, J. E., & Zheng, Y. Y. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106125 · Cited by 22 · see citing works
Qi, F., Zuo, Z., Hu, K., Wang, R., Wu, T., Liu, H., Tang, J., Wang, Q., Xie, Y., Tan, L., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02097-w · Cited by 23 · see citing works
“VEGF-A can also increase hippocampal neurogenesis in young mice [23, 24], and signal to the hippocampal endothelial cells, which are essential sensors of age-related circulatory factors [25].”
BackgroundCa2+ homeostasis in brain microvascular endothelial cells
Stoica, R., Rusu, C. M., Staicu, C. E., Burlacu, A., Radu, M., & Radu, B. M. (2021) · International review of cytology · doi:10.1016/bs.ircmb.2021.01.001 · Cited by 23 · see citing works
The vasculature of neurogenic niches: Properties and function
Karakatsani, A., Álvarez-Vergara, M. I., & de Almodóvar, C. R. (2023) · Cells and Development · doi:10.1016/j.cdev.2023.203841 · Cited by 24 · see citing works
Chum, P. P., Hakim, M. A., & Behringer, E. J. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-215223 · Cited by 21 · see citing works
“With an exception of highlighting cerebrovascular endothelial cells as a sensitive regulatory interface between the circulatory system and the brain [19], a paucity of information remains for cerebrovascular –omics of aging and/ or AD.”
Cheung, V., Chung, P., Bjorni, M., Shvareva, V. A., Lopez, Y. C., & Feinberg, E. H. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110131 · Cited by 21 · see citing works
“annotate clusters based on the expression of known marker genes, separating inhibitory and excitatory neurons, endothelia, and glia (Figure 2B) (Chamling et al., 2021; Chen et al., 2020; Hammond et al., 2019; Hasel et al., 2017; He et al., 2016; Traag et al., 2019; Yao et al., 2021).”
Single‐cell RNA‐seq reveals interferon‐induced guanylate‐binding proteins are linked with sarcopenia
Peng, Z. Y., Zhang, R., Kuang, X., Chen, Y., Niu, S., Du, Y., Lu, D., Li, S., Teng, Z., & Lu, S. (2022) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13091 · Cited by 21 · see citing works
“Endothelial3 expressed Clu and Stmn2 (Figure S2C), hinting their arterial origins.(18,19)”
BackgroundVascular endothelial cells: a fundamental approach for brain waste clearance
Wei, H., Jiang, H., Zhou, Y., Xiao, X., Zhou, C., & Ji, X. (2022) · Brain · doi:10.1093/brain/awac495 · Cited by 20 · see citing works
Wang, J., Guo, Y., Xu, D., Cui, J., Wang, Y., Su, Y., Liu, Y., Shen, Y., Jing, X., & Bai, W. (2022) · Scientific Reports · doi:10.1038/s41598-022-26831-6 · Cited by 21 · see citing works
Meiners, F., Hinz, B., Boeckmann, L., Secci, R., Sueto, S. O. B., Kuepfer, L., Fuellen, G., & Barrantes, I. (2024) · Scientific Reports · doi:10.1038/s41598-024-55870-4 · Cited by 21 · see citing works
Sweet, D. R., Padmanabhan, R., Liao, X., Dashora, H. R., Tang, X., Nayak, L. V., Jain, R., Val, S. D., Vinayachandran, V., & Jain, M. K. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.121.024303 · Cited by 20 · see citing works
“42 Identification of unique regulators to explain EC transcriptional heterogeneity remains to be fully explored.”
The blood–brain barrier as a treatment target for neurodegenerative disorders
Rust, R., Sagare, A. P., Zhang, M., Zloković, B. V., & Kisler, K. (2025) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2025.2480654 · Cited by 20 · see citing works
“As observed in humans, in rodent models aging leads to changes in neurovascular morphology, BBB permeability, and function which may be due in part to changes in NVU cells including endothelial cells, mural cells, and astrocytes [12,59– 61].”
Mbagwu, S. I., & Filgueira, L. (2020) · Brain Sciences · doi:10.3390/brainsci10010031 · Cited by 20 · see citing works
“These changes have been suggested to influence the nature and function of the BBB [27,28].”
BackgroundPediatric Brain Tumours: Lessons from the Immune Microenvironment
Yao, B., Delaidelli, A., Vogel, H. S., & Sorensen, P. H. B. (2023) · Current Oncology · doi:10.3390/curroncol30050379 · Cited by 21 · see citing works
Endothelial type I interferon response and brain diseases: identifying STING as a therapeutic target
Duarte, N., Shafi, A. M., Penha‐Gonçalves, C., & Pais, T. F. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1249235 · Cited by 20 · see citing works
“Activation of type I signaling in endothelial cells may be triggered by infection but it is also caused by gene mutations, response to cellular stress and changes in inflammatory and ageing-related circulating factors (Chen et al., 2020).”
Background
- Authors
- Chen, M. B., Yang, A. C., Yousef, H., Lee, D., Chen, W., Schaum, N., Lehallier, B., Quake, S. R., & Wyss-Coray, T.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- Quake, Stephen R.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 30
- Issue
- 13
- Pages
- 4418-4432.e4
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7292569
- OpenAlex
- W3014940784
- Cited by
- 233
- References
- 92
- Citations by year
- 2026: 34 · 2025: 42 · 2024: 28 · 2023: 31 · 2022: 43 · 2021: 42 · 2020: 11 · 2019: 2
- FWCI
- 11.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute on Aging (T32-AG0047126, F32-AG051330, R01-AG059694, DP1-AG053015)
- Wu Tsai Neurosciences Institute, Stanford University
- U.S. Department of Veterans Affairs (UL1 TR001085)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- brain endothelial cells, blood-brain barrier, aging, plasma transfusion, capillary endothelial cells, hippocampus, innate immunity, oxidative stress response, transcriptome, neuroinflammation, adult neurogenesis, cognitive function
- MeSH terms
- Aging, Animals, Arteries, Blood Circulation, Brain, Capillaries, Lipopolysaccharides, Male, Mice, Inbred C57BL, Transcription, Genetic, Veins, Endothelial Cells, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
