bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.08.14.670255

Aging of the blood-brain barrier: Metabolic signatures of mouse brain endothelial cell senescence

Tahir, A.·Balasubramanian, H. B.·Kahr, D.·Haage, F.·Zille, M.
View original source ↗Export metadata ↓

Abstract

The blood-brain barrier (BBB) declines with age, with endothelial senescence implicated as a contributor, yet its metabolic features remain incompletely defined. We induced senescence in mouse brain endothelial cells (BECs) using the chemotherapeutic doxorubicin and the oxidative stress mediator hydrogen peroxide and performed untargeted mass spectrometry of cell lysates and supernatants. Senescence was confirmed by increased senescence-associated {beta}-galactosidase activity and elevated cyclin-dependent kinase inhibitors p16 and p21, along with increased Il-6 mRNA as senescence-associated secretory phenotype marker. At the BBB structural level, occludin was consistently reduced, ZO-1 decreased with H2O2 (with a similar trend under doxorubicin), and claudin-5 showed a variable, non-significant reduction, indicating target- and inducer-specific junctional remodeling. Pathway mapping highlighted prominent remodeling of lipid metabolism (including glycerophospholipids, sphingolipids, acylcarnitines) and amino-acid pathways, with both shared and inducer-specific shifts. These discovery-stage in vitro results recapitulate several metabolites previously associated with senescence across tissues and nominate additional candidates for hypothesis testing. To increase mechanistic and translational relevance, we outline a staged roadmap: validation in advanced multicellular and flow-based BBB models followed by in vivo studies, with attention to route-specific BBB readouts. Overall, this work provides a curated snapshot of metabolic remodeling in brain endothelial senescence that co-occurs with selective tight-junction alterations relevant to BBB aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/670255v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1644442org.highwire.dtl.DTLVardef@1bd5821org.highwire.dtl.DTLVardef@1e4efd5org.highwire.dtl.DTLVardef@13d942d_HPS_FORMAT_FIGEXP M_FIG C_FIG Mouse brain endothelial cells exposed to doxorubicin (Dox) or hydrogen peroxide (H2O2) underwent senescence ({uparrow}SA-{beta}-gal activity, p16/p21 expression), accompanied by selective reductions in tight-junction proteins. Untargeted mass spectrometry profiled metabolites in cell lysates and supernatants. Lipids, followed by amino acid metabolites, comprised the largest share of alterations, highlighting these pathways as major components of metabolic reprogramming associated in endothelial senescence.

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Tahir, A., Balasubramanian, H. B., Kahr, D., Haage, F., Zille, M.. 2025-08-18. Aging of the blood-brain barrier: Metabolic signatures of mouse brain endothelial cell senescence. https://doi.org/10.1101/2025.08.14.670255

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Connexin 40 deficiency alters the temporal profile of postictal oxygen dynamics following focal seizures.

Epilepsy is increasingly recognized as a disorder involving both neuronal and vascular dysfunction. While connexin signaling has been implicated in epileptogenesis, the contribution of vascular connexins to seizure associated cerebrovascular pathology remains poorly understood. Connexin40 (Cx40) is an endothelial gap junction protein that plays a crucial role in vascular communication and blood-flow regulation. Seizures induce dynamic changes in cerebral perfusion and oxygenation, including prolonged postictal hypoperfusion/hypoxia. To determine whether Cx40 influences postictal hypoxia following focal seizures, we examined seizure characteristics and postictal oxygen dynamics in Cx40 knockout (Cx40-/-) mice using an established focal hippocampal seizure model. Electrically kindled seizures were elicited in wild-type and Cx40-/- mice, and local hippocampal tissue oxygenation was continuously monitored before and after seizure induction. Seizure duration did not differ between genotypes, indicating comparable seizure severity. Interestingly, Cx40 deletion altered the temporal pattern of postictal oxygen recovery, producing greater early hypoxia and a delayed secondary rebound in pO2 despite similar peak oxygen levels and overall hypoxic burden. These findings demonstrate that loss of Cx40 selectively alters the temporal profile of postictal oxygen dynamics without affecting seizure duration. Taken together, the results suggest that endothelial gap junctional communication contributes to postictal vascular recovery and identify Cx40 as a potential modulator of seizure associated neurovascular dysfunction.

neuroscience↗
bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗
bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗