The funded projects address several complementary therapeutic strategies. Ruud Wijdeven (Candidate center) and Iwan de Esch (VU AIMMS) focus on compounds that may block the cellular uptake of toxic APOE4, a major genetic risk factor for Alzheimer’s disease. Iwan de Esch (VU AIMMS) and Wiep Scheper (Molecular Neurodegeneration group) are working on dual inhibition of PDE4 and PDE7, with the aim of combining anti-inflammatory and cognition-supporting effects in a single therapeutic strategy. Rik van der Kant (Dementia Discovery group) is investigating whether existing drugs can reduce fibronectin levels and help protect the blood–brain barrier in APOE4 carriers.

Outside of the CNCR, a fourth collaborative project between Rob Leurs (VU AIMMS) and Elga de Vries (Amsterdam UMC, MCBI) investigates ACKR3 as a target to reduce harmful immune cell entry into the brain and limit neuroinflammation.

The awarded projects highlight the urgency for development of novel and more effective therapies for AD, and the need for cross-disciplinary approaches spanning both chemistry and biology to develop such therapies.

The HypoGluTx project centers on disorders associated with genes including GRIN2B, SHANK3, STXBP1, and CACNG2, which converge on disrupted glutamatergic neurotransmission. By targeting this shared biological mechanism, the consortium aims to identify scalable treatment strategies across genetically distinct conditions.

Neurospector contributes its platform of human iPSC-derived neuronal models and high-content functional readouts to evaluate compound efficacy in a clinically relevant context. The project will assess both established compounds and new candidates identified through data-driven approaches, prioritizing molecules with known safety profiles to enable rapid translation.

“We see this as a step toward a new generation of precision therapies, where shared biology across rare disorders can unlock broader impact for patients,” says Claudia Persoon, Head of Neurospector.

This collaboration highlights Neurospector’s role as a translational partner in bridging discovery science and preclinical drug development, supporting the generation of IND-ready data packages for rare neurological indications.

SNAREopathies are a group of recently recognized rare neurodevelopmental disorders caused by mutations in eight genes that together drive secretion of chemical signals in the brain. Within 20 years, SNAREopathy incidence rose from zero to one of the most prevalent rare diseases to date (1:30k), producing a phenomenal unmet need.

The iSNARE consortium aims to change this situation by combining cellular assays based on available IPSC-derived SNAREopathy patient neurons with in vivo assays using available SNAREopathy mouse models. These in vitro and in vivo assays are combined in a standardized, integrated framework to systematically test and compare candidate treatments in three phases of development:

(i) four small molecules currently tested off label in small patient cohorts (replication study)

(ii) 6-10 emerging candidates (small molecule, antisense oligonucleotides)

(iii) novel compounds designed de novo by iSNARE in silico modeling using validated SNARE protein templates.

This systematic, multi-level approach will produce a unique data set that quantitatively compares effectivity and potency of most candidate treatments currently on the radar and firmly establishes the most promising ones. The strong connection to national treatment sites in nine EU countries + Israel ensures their rapid dissemination to clinical practice. The standardized array of in vivo and in vitro assays developed here provides a valuable framework for the assessment of future candidate therapies.

The iSNARE consortium (3 female, 4 male partners, 6 countries) brings together some of the best-cited scientists in the SNARE field and human neuron pioneers with experienced SNAREopathy mouse model experts, in silico modelling experts and patient organizations in nine EU countries + Israel. Together, this complementary expertise and patient participation warrant a project design that exploits the most recent scientific advances to promote new therapy development that maximally serves the patients’ needs.

In Alzheimer’s disease (AD) intraneuronal aggregation of the protein tau leads to neurodegeneration. Previous studies showed that tau aggregation reduces protein synthesis and that restoring protein synthesis improves neuronal survival. At the same time, tau aggregation is also accompanied by the presence of lysosomal structures known as granulovacuolar degeneration bodies (GVBs) in AD patients. Up until now, it remained unclear whether these structures contribute to neurodegeneration or instead protect the neuron.

In the current study -supported by Hersenstichting/Coby van Nieuwkerkfonds and NWO-, Jasper and co-authors demonstrate that the kinase CK1δ plays a key role in GVB formation: inhibiting CK1δ almost completely ablated GVB formation, while overexpression of CK1δ nearly doubled the amount of GVB+ neurons. They furthermore showed that the accumulation of CK1δ and other cargo into the GVB depends on the autophagic machinery.

Moreover, the researchers showed that also in their model, tau aggregation drives neurodegeneration, which is paired with a reduction in protein synthesis. They show that the increased protein synthesis in GVB+ neurons is most likely due to an increase in ribosomal biogenesis factors, absent in GVB- neurons. The researchers also found that tau aggregation reduces the immediate-early-gene response of cFOS and ARC; 2 proteins important in LTP and memory formation. Again, GVB+ neurons showed a similar response as neurons without tau aggregation.

This study identified CK1δ as an upstream regulator of GVB formation that confers a protective neuron-specific stress response to tau pathology, offering new insights into neuronal resilience upon tau aggregation. This may represent a promising avenue for therapeutic strategies by enhancing neuronal resilience pathways.

Brain disorders caused by large effect mutations in single genes often present unexplained large symptom diversity, even among carriers of the same mutation. In the new study, a collaboration between FGA and the university of Copenhagen, the authors examined genetic interactions as a possible explanation for this diversity for SNAREopathies, a group of common neurodevelopmental disorders caused by de novo genetic variation in genes that together drive secretion of chemical signals in the brain. SNAREopathies are characterized by a striking phenotypic diversity, including different types/degrees or absence of seizures, developmental delay and intellectual disability.

The authors tested the hypothesis that large phenotypic diversity is caused by non-linear genetic interactions between two or more functionally related genes by combining validated SNAREopathy mouse models and comparing phenotypic diversity between single and double mutants at the synaptic, network, system and behavioral level. Single Stxbp1 and Snap25 mutant animals showed EEG- and motor abnormalities, but no seizures, as reported before. In contrast, double mutants exhibited extreme diversity in seizure phenotypes. Some mice had lethal generalized seizures, frequent and complex epileptiform EEG activity and thalamic hyper-excitability as indicated by increased cFos staining, while other mice of the same genotype showed no detectable abnormalities, no increased cFos staining and a normal life span. The surviving double mutant mice showed phenotypes not more severe than single mutants at the synaptic, network, and behavioral level.

The authors also present a theoretical framework to quantitatively explain the observed non-linear effects and extrapolate the conclusions to symptoms diversity in human patients. This study provides a proof of concept for how modifying genes in the patient genome enhance phenotypic diversity.

The study can be found here.

 

Representing the Molecular Neurodegeneration group, she built on previous findings from the lab showing that astrocytes display stress responses to intraneuronal tau pathology. Using human cellular models, she identified a mechanistic link between increased oxidative stress and the activation of the integrated stress response. She further investigated the physiological consequences for astrocytes.

These results provide new insights into how astrocytes respond and adapt to intraneuronal tau pathology, which could potentially elucidate targets for therapeutic intervention.

Thijmen Ligthart from the Molecular Neurodegeneration lab has been awarded the presenter prize at the annual meeting of the Dutch Protein Aggregation Network (DPAN), a national platform that brings together researchers studying protein misfolding and aggregation.

In his presentation, Thijmen described recent findings from the lab demonstrating that granulovacuolar degeneration bodies (GVBs) identify a neuronal state that is resilient to tau-induced impairment of protein synthesis. Using cellular models of tau pathology, this work reveals that GVB formation is associated with the preservation of translational capacity, leading to increased survival under proteostatic stress.

These results provide new insight into how neurons adapt to tau-induced neurodegeneration and suggest that GVBs may serve as a marker of cellular coping mechanisms in tauopathies.

Neuroscientsts Angela Getz and Maxime Malivert (FGA/CNCR), and their colleagues in France, Canada and the U.K. discovered the new insights, as published in Neuron. These results open up new avenues of research.

Using new molecular tagging and advanced imaging approaches, the researchers visualised the molecules that transmit signals at the receiving side of the synapse. This approach allowed them to track these receptors in real time in intact brain tissue and follow their movements across the surface of synapses. The same approach also allowed them to manipulate the mobility of these molecules and ask how their mobility contributes to information processing.

Synapses have their own built-in gain control
The researchers observed that this mobility plays a crucial role when synapses are activated at high frequencies. Under normal conditions, the receptors temporarily desensitise after repeated activation. Their mobility allows new receptors to move into the synapse and replace those that have become desensitised, thus maintaining strong signal transmission. When their mobility is blocked, desensitised receptors remain trapped in the synapse and transmission decreased sharply, acting as a brake.

This mechanism therefore acts as a gain control; an acceleration or deceleration system integrated into each synapse. Remarkably, not all synapses rely on this principle in the same way. Depending on their architecture and molecular properties, some are very sensitive to receptor mobility, while others are much less so. Each synapse thus possesses its own “dynamic signature” of information processing.

Receptor mobility opens new paths for brain research
The researchers also show that when the brain stores new information, it does so by modifying this receptor mobility. These results open up new avenues of research: many physiological or pathological factors – stress, aging, neurodegenerative diseases – may be influenced by modulating receptor mobility.

Assistant professor Angela Getz, post doc Maxime Malivert and their team have established these advanced imaging setups and techniques in the VU Research Building. They currently investigate how architecture and molecular properties of different synapses determines their “dynamic signature”. They also train master students to operate the set up and visualize individual molecules in intact brain tissue in real time.

The human brain has unique cognitive abilities compared to animals. However, it is also vulnerable to diseases that bring cognitive decline and neurodegeneration, such as Alzheimer’s. What makes the human brain so different? Neuroscientist Goriounova’s team thinks the answer lies in the function of neurons in our brains. Over the course of evolution, our neurons could have developed properties to process information faster and more efficiently in a larger brain, but which also made the neurons more vulnerable.

Neurons
Previously, Goriounova showed that the human brain holds specialized neuron types with distinct properties associated with IQ scores. These neurons could be crucial to human cognition because they are selectively lost in cognitive impairment. How these neurons function and form connections in the human brain is still unknown.

In her ERC proposal, Goriounova will test her prediction that cortical computation in the human brain depends on a highly interconnected network of these special types of neurons, which form fast and strong connections and can be fine-tuned by specific receptors to increase computational power.

Live brain tissue studies
These questions can only be investigated in adult living human neurons in their intact networks. This is extremely challenging because of the difficult access to human brain cells. Goriounova therefore collaborates with several hospitals in the Netherlands treating people with tumors or epilepsy. During surgical treatment, the neurosurgeon also removes a small piece of healthy cortical tissue to access the focus of the disease. This human brain tissue can be kept alive and used to study how neuronal cells function in their intact connections.

By collecting preoperative data from the same patients, the team can now link neuronal function to live brain network activity and cognitive scores of these patients. These methods make it possible to answer the question of the specialized function of human neurons relevant to cognition.

Consolidator Grant
The ERC uses the Consolidator Grant to support outstanding principal investigators for a period of five years at the career stage when they may still be setting up their own independent research team or program. Goriounova will receive €2 million for her project.

 

Alzheimer Nederland awarded €121,650 to Dr. Douglas Wightman (Complex Trait Genetics) to investigate genetic and environmental prediction of Alzheimer’s disease.

Alzheimer’s disease presents later in life but the biological processes that contribute to the disease development start well before symptom onset. Early prediction of Alzheimer’s disease risk before symptom onset would be beneficial in directing individuals to care earlier and may allow for more effective treatment.

In this project, Douglas will use machine learning methods to combine genetic risk and environmental risk to better predict Alzheimer’s disease. Models of genetic risk will be based on recent large genome wide association studies. There is a specific aim to create a minimal model that limits the number of features for easy clinical implementation.

This research aims to priortise genetic and environmental factors that can accurately