BRAIN HEALTH; Dysmetabolism, Brain Aging and Neuroinflammation
CONTRACT SERVICE, TECHNOLOGIES OPEN FOR PARTNERING
Unlocking New Frontiers in Brain Health: Ldlr(-/-).Leiden Preclinical Body-Brain Model
The brain does not function in isolation systemic metabolic and inflammatory conditions deeply impact central nervous system (CNS) health.
To bridge the translational gap between animal models and human pathology, TNO has developed the patented Ldlr(-/-).Leiden mouse, a humanized preclinical body-brain model designed to study neurodegenerative mechanisms, cerebrovascular impairment, and systemic interactions.
Key Technological Highlights & Model Features
● Humanized Genetic Background & Translational Relevance
> Incorporates 262 high-impact human SNPs, mimicking key human disease mechanisms, pathologies, biomarkers (such as GFAP, NF-L, and Tau), and drug responses across obesity, insulin resistance, and cardiovascular diseases.
● Dual Metabolic-Inflammatory Phenotypes (Aging vs. Diet-Induced Obesity)
> Aging Model (Chow): Replicates natural age-related cognitive decline and progressive neuroinflammation.
> Obesity/Metabolic Model (HFD): Accelerates chronic systemic and neuro-inflammation, structural brain changes, and cognitive deficits.
> Both phenotypes can be modulated via pharmaceutical and nutritional interventions.
● In-Depth Biomarkers & Multi-Omics Readouts
> Advanced Neurohistopathology & AI Analysis: Accurate quantification of neuronal loss, astrogliosis (GFAP), and microgliosis (IBA-1, CD68, TREM2).
> Spatial & Molecular Omics: Spatial lipidomics (MALDI-MSI targeting >300 specific lipids), oxylipins, transcriptomics, and cortical lipid/ketone body metabolic profiles.
> Translational Human-like Biomarkers: Replicates microglial immunophenotypic shifts and lipid profiles observed in human neurodegenerative disorders and Alzheimer's disease.
● Cerebral Small Vessel Disease (CSVD) & Blood-Brain Barrier (BBB) Dysfunction
> Models key hallmarks of CSVD, including endothelial dysfunction (GLUT-1 loss), reduced cerebral blood flow (CBF), vascular inflammation (E-selectin, VCAM-1), tight junction impairment (ZO-1, Claudin-5), and BBB leakage (in vivo DCE-MRI & NaFl tracer studies).
● Peripheral-Central Nervous System Interactions
> Exhibits peripheral nerve demyelination and damage (sciatic nerve pathology) under hyperinsulinemic/obese conditions, offering critical insights into diabetic neuropathic pain and peripheral-to-central neurodegeneration.
● Comprehensive Structural, Functional & Behavioral Readouts
> Evaluated via non-invasive in vivo MRI (structural/white matter integrity, fractional anisotropy, cortical thinning) alongside validated cognitive/behavioral testing (Object Recognition Test, Morris Water Maze).
Call for Collaboration; Brain Health PPP (PPP)
We are actively seeking academic and industrial partners worldwide to participate in our Brain Health Public-Private Partnership (PPP).
GOAL： To evaluate innovative therapeutics, preventive interventions, and nutritional strategies aimed at preserving brain health, restoring vascular/BBB integrity, and halting neurodegeneration.
What We Offer:Access to a highly characterizable, human-relevant preclinical body-brain model, robust multi-omics/histological readouts, and a collaborative framework aimed at joint high-impact scientific publications.
Download more information (presentation slides in pdf):
□ TNO's BrainHealth_preclinical_LdlrKO.Leiden
Publication:
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Semaglutide and Exercise Synergy in Obesity: Preserving Muscle Mass and Uncovering Organ Crosstalk. Diabetes Metab J Published online Jul, 2026
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Impact of voluntary exercise on obesity-induced brain pathology: Insights from a multimodal approach in male Ldlr-/-.Leiden mice. Brain Behav Immun. Aug 2026
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Identification and Characterization of a Translational Mouse Model for Blood-Brain Barrier Leakage in Cerebral Small Vessel Disease. Int J Mol Sci. Jul 2025
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Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice impacts adipokine secretion, plasma free fatty acids, and improves cerebrovascular health. PLoS One. Oct 2025
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Obesity accelerates age-related memory deficits and affects brain connectivity and white matter tract integrity in Ldlr-/-.Leiden mice. Brain Behav Immun Health. Apr 2025
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Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr-/-.Leiden mice.Int J Obes (Lond). Feb 2022
AI BRAIN PATHOLOGY : Brain AI
TNO's AI histopathology algorithms turns brain sections into objective, region-level read-outs of neurodegeneration and neuroinflammation.
Quantify brain sections faster and more accurately with AI
Our AI reads whole-slide images of stained brain sections, segments the brain regions, and then detects individual cells. The result is a reproducible quantification that removes reader variability and scales to large preclinical cohorts.
Multi marker readouts
Neuron detection and density (NeuN)
Every NeuN+ neuron is detected and counted within its region, giving objective neuronal-density and neuron-loss read-outs. With more than 30k neurons per slice, such a measurement would be infeasible by hand.
Microglial activation (Iba1)
Iba1+ microglia are detected across the section to quantify microglial activation and the regional spread of neuroinflammation.
Cortical thickness
The AI-segmented cortex is measured directly into reproducible cortical-thickness maps across the whole section, a structural read-out infeasible to produce by hand at scale.
Why it matters
● Faster and cost-saving: shorter turnaround than manual scoring of large cohorts.
● Replicates the pathologist: counts cells and estimates affected tissue the way an expert scores it.
● Reads 100% of the section: densities and areas computed over the whole tissue, not a sampled subset.
● Markers beyond manual review: per-region cell counts and densities that are infeasible by hand.
● Standardized and reproducible: removes inter- and intra-reader variability.
Gut-Liver-Brain Axis Research to Improve Metabolic Health, "GLoBAL" (ongoing project, Open for partnering)
● Overview；
Investigation of Gut-Liver-Brain Axis in severe obese patients undergoing bariatric surgery（～n=150) with extensive characterization of tissue biopsies and systems biology.
Extensive neuroimaging (MRI), cognition tests, plasma and microbiota analysis over time (pre-operation, hospitalization and post-operation).
● Readout and Samples；
> Brain; Cognition, Behaviour test, Brain fMRI scan.
> Samples (n=500).
> Tissue; Liver, Adipose tissue, jejunam.
> Plasma; Lipidomics, Adipokine, Hepatokines, Bile acids, etc.
> Microbiota; Feces, Mucosal swab; Stomach, jejunum.
● Tests conducted；
> NeuroPhysiological test; MoCA, COWAT, IQ, Working memory, Episodic memory, TAP.
> Behaviour; Scores of Impulsivity, Motivation, Depression, GI complaint, etc.
> GI complaints (e.g. GSRS and IBS-SSS scores) to evaluate diarrhea, obstipation and others.
● Invitation to analyse specific health aspect using the samples in stock as the followings;
> Liver (histology, transcriptomics).
> Visceral adipose tissues.
> Jejunum, gut permeability.
> Mucosal & feces microbiota.
> Plasma.
> SCFA, amino acids, lipids, bile acids, Vitamins, etc.
● Opportunities to assess relation between MB and Brain.
> Choose interaction of interest (e.g. microbiota to long-term memory, or gut permeability to cognition tests).
> Use available data or eventually measure additional parameters.
> Check for correlations or associations.
> Identify critical body parameters that correlate with brain health.
> Analysis over time, e.g. microbiota traits that predispose a person to develop GI pain complaints.
Publication:
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Sustained Improvement of Cognition, Mood and Plasma Markers Three Years After Metabolic Bariatric Surgery. The BARICO Study
Obes Surg. Sep 2025.
Emma Custers, Debby Vreeken, Robert Kleemann, Roy P C Kessels, Esmee Tijman Op Smeijers, Joachim Hog Mortensen, Martine C Morrison, Eveline Gart, Maximilian Wiesmann, Eric J Hazebroek, Amanda J Kiliaan.
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Metabolic dysfunction-associated steatotic liver disease is associated with effects on cerebral perfusion and white matter integrity
Heliyon. Sep 2024.
Florine Seidel, Debby Vreeken, Emma Custers, Maximilian Wiesmann, Serdar Ozsezen, Wim van Duyvenvoorde, Martien Caspers, Aswin Menke, Martine C Morrison, Lars Verschuren, Marco Duering, Eric J Hazebroek, Amanda J Kiliaan, Robert Kleemann.
□ The long-term effect of metabolic bariatric surgery on innate immune cell phenotype and function Int J Obes Aug 2025.
van Tuijl J, Vreeken D, Broeders W, Cossins B, van Emst L, Seidel F, Stienstra R, Li Y, Joosten LAB, Netea MG, Hazebroek EJ, Kleemann R, Kiliaan AJ, Bekkering S, Riksen NP.
□ Gastrointestinal complaints after Roux-en-Y gastric bypass surgery. Impact of microbiota and its metabolites. Helyon Nov, 2024.
Emma Custers, Yonta G.R. van der Burgh, Debby Vreeken, Frank Schuren, Tim J. van den Broek, Lars Verschuren, Ivo de Blaauw, Mark Bouwens, Robert Kleemann, Amanda J. Kiliaan, Eric J. Hazebroek.
Human Body Brain Interaction Platform; Model of Stress-induced Cognition Impairment
● Overview；Unique Body-Brain Technology for mental health, cognition, stress, performance, wellbeing
to investigate the efficacy (or adverse effect) of various types of test product or factor such as medicine, nutrient, lifestyle, and psycho-social.
> Rapid (2W) human studies to test interventions
> Subject; Healthy volunteer
●Test option；
> Psychomotor Vigilance Test; Attention/Alertness
> Working Memory Task; Reasoning and Decision making
> Cognitive Flexibility Task; Adaptation, Task switching
> Attention Network test; Alertness, Orientation
> Affective Stroop Task; Processing of Emotional info
> Driving simulator test
●Measures；
> Brain：EEG, fNIRS(functional Near-Infrared Spectroscopy)
> Eye：Pupil size, Blink, Eye tracking
> Blood：Cytokines, Cortisol, Metabolic, Inflammation markers
> Heart：ECG, HRV (Heart rate variability)
> Microbiota, Microbiota Metabolite
> Wearable device: Daily monitoring, EMA, ESM
> Reaction time, Acuracy, Cognitive performance
> Skin conductance, Arousal, Body Posture, Activity
> Questionnaire
●Stressors ;
> Cognitive load, Noise, Cold water, Climate chamber
> Sleep deprivation, Emotional stress, Social stress
> Mild electric shock, Hypoberic room
> Aerobic exercise, Obstacle course
●Opportunities
> Novel prediction algorithms (e.g., early alert systems warn for acute lapses in performance)
> Identify novel treatments to increase cognitive performance and alertness
> Identify novel treatments (e.g. supplements) that help to cope with little sleep
● Publication
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Additive effects of depression and obesity on neural correlates of inhibitory control. J Affect Disord. Oct 2024
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Seven robust and easy to obtain biomarkers to measure acute stress. Brain Behavior and Immunity - Health, July 2024
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Understanding the combined effects of sleep deprivation and acute social stress on cognitive performance using a comprehensive approach. Brain Behav Immun Health. Nov 2023
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Impact of White Adipose Tissue on Brain Structure, Perfusion, and Cognitive Function in Patients With Severe Obesity: The BARICO Study Neurology. Feb 2023
