Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

Yousef, Hanadie; Czupalla, Cathrin J.; Lee, Davis; Chen, Michelle B.; Burke, Ashley N; Zera, Kristy A; Zandstra, Judith; Berber, Elisabeth; Lehallier, Benoit; Mathur, Vidhu; Nair, Ramesh V.; Bonanno, Liana; Yang, Andrew; Peterson, Todd C.; Hadeiba, Husein; Merkel, Taylor; Körbelin, Jakob; Schwaninger, Markus; Buckwalter, Marion S.; Quake, Stephen R.; Butcher, Eugene C.; Wyss‐Coray, Tony

doi:10.1038/s41591-019-0440-4

Cited by 307 publications

(305 citation statements)

References 79 publications

(104 reference statements)

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…The practical pharmacological approach we demonstrated complements the recent exciting discovery that young plasma infusion can partially reverse ageing-associated EC transcriptomic alterations 76 . In fact, apart from the reversal of expression changes in the aged brain endothelium, GLP-1R agonist treatment and young plasma infusion appear to share several functional benefits in animal models, such as amelioration of neuroinflammation 32,77 , rescuing synaptic plasticity deficits and cognitive benefits in aged or AD mouse 78,79 . Further studies are required to clarify the exact loci of actions for GLP-1R agonists.…”

Section: Discussionmentioning

confidence: 99%

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zhao

Vong

et al. 2019

Preprint

View full text Add to dashboard Cite

With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail 1,2 , yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases 3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed -the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions [8][9][10][11][12][13][14][15][16][17] . Furthermore, an overrepresentation of Alzheimer's disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with 2 exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

show abstract

Section: Discussionmentioning

confidence: 99%

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zhao

Vong

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…4h,i). Of note, to test lipid droplet formation in BV2 cells and its effects on phagocytosis in a system that mimics the aging environment, we treated BV2 cells with aged plasma, which has been shown to activate microglia and to trigger brain aging 82 . Indeed, aged plasma induced lipid droplet formation, and again, cells with high numbers of lipid droplets showed significantly less Zymosan uptake ( Supplementary Fig.…”

Section: Lam Have Phagocytosis Deficitsmentioning

confidence: 99%

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

Marschallinger

Iram

Zardeneta

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Microglia become progressively activated and seemingly dysfunctional with age, and genetic studies have linked these cells to the pathogenesis of a growing number of neurodegenerative diseases. Here we report a striking buildup of lipid droplets in microglia with aging in mouse and human brains. These cells, which we call lipid droplet-accumulating microglia (LAM), are defective in phagocytosis, produce high levels of reactive oxygen species, and secrete proinflammatory cytokines. RNA sequencing analysis of LAM revealed a transcriptional profile driven by innate inflammation distinct from previously reported microglial states. An unbiased CRISPR-Cas9 screen identified genetic modifiers of lipid droplet formation; surprisingly, variants of several of these genes, including progranulin, are causes of autosomal dominant forms of human neurodegenerative diseases. We thus propose that LAM contribute to agerelated and genetic forms of neurodegeneration.

show abstract

“…Especially interesting are Vcam1 and periostin (Postn), which both show exceptional correlation across several organs ( Figure 4C-J). Vcam1 was recently implicated as a critical mediator of brain aging by old plasma 17 , and the loss of Postn in adipose tissues contributes to impaired lipid metabolism 18 . Throbospondin-4 (Thbs4), here decreasing with age and highly correlated with gene expression in muscle, was also recently discovered as a young blood-enriched protein that promotes synapse formation 19 .…”

mentioning

confidence: 99%

The murine transcriptome reveals global aging nodes with organ-specific phase and amplitude

Schaum

Lehallier²,

Hahn³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Aging is the single greatest cause of disease and death worldwide, and so understanding the associated processes could vastly improve quality of life. While the field has identified major categories of aging damage such as altered intercellular communication, loss of proteostasis, and eroded mitochondrial function 1 , these deleterious processes interact with extraordinary complexity within and between organs. Yet, a comprehensive analysis of aging dynamics organism-wide is lacking. Here we performed RNA-sequencing of 17 organs and plasma proteomics at 10 ages across the mouse lifespan. We uncover previously unknown linear and non-linear expression shifts during aging, which cluster in strikingly consistent trajectory groups with coherent biological functions, including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Remarkably, these gene sets are expressed similarly across tissues, differing merely in age of onset and amplitude. Especially pronounced is widespread immune cell activation, detectable first in white adipose depots in middle age. Single-cell RNA-sequencing confirms the accumulation of adipose T and B cells, including immunoglobulin J-expressing plasma cells, which also accrue concurrently across diverse organs. Finally, we show how expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to aging of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter-and intra-organ progression of aging, thereby providing a foundation to track systemic sources of declining health at old age.

show abstract

Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1

Cited by 307 publications

References 79 publications

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Lipid droplet accumulating microglia represent a dysfunctional and pro-inflammatory state in the aging brain

The murine transcriptome reveals global aging nodes with organ-specific phase and amplitude

Contact Info

Product

Resources

About