Research on information processing in the brain previously focused mainly on communication between neurons. However, in recent years it has emerged that a non-neuronal cell, the astrocyte, which was previously seen as a kind of support cell of your brain, also plays a role in memory and cognition. Astrocytes do this by forming connections with both neurons and blood vessels in the brain. Which molecules are involved in these connections is largely unknown. In SUPERGLUE we use advanced techniques to map these molecules and cellular interactions, taking an important step in our understanding of information processing by the brain.

The diagnosis of young-onset disorders causing dementia, such as young-onset Alzheimer’s disease (YOAD) and Frontotemporal dementia (FTD) is often delayed since these disorders often present with non-memory symptoms, such as problems with behaviour, social cognition, language, or perception. These symptoms have been associated with focal degeneration of specific cortical brain regions, but we still lack an understanding of why and how these specific regions are affected, while this information can be crucial for the development of treatment. Our multidisciplinary YOD-MOLECULAR project aims to i) improve the diagnosis of FTD and YOAD by creating a novel Young-Onset Dementia (YOD) test battery that captures affected non-memory domains; ii) develop data-driven models that define the most vulnerable and earliest affected brain regions in non-memory YOAD and FTD phenotypes; iii) identify from these vulnerable regions, the underlying disease mechanisms at the molecular and cellular level in YOAD and FTD, and iv) integrate clinical and biological data using Artificial Intelligence (AI) to generate comprehensive and meaningful clinical-biological YOD subtypes. YOD-MOLECULAR interconnects four work packages led by clinicians, language and AI experts, and basic scientists together with biotech companies, patient representatives, young entrepreneurs, ethic experts, and knowledge institutes. Throughout YOD-MOLECULAR, AI addresses specific challenges, relating to clinical, pathological, neuroimaging and molecular data modelling. Through earlier and accurate diagnosis and the identification of targets for biomarker and drug development we facilitate individualised disease management, reduction of healthcare costs, and improved quality of life.

Urgency: An estimated 179 million individuals in Europe are currently suffering from a brain disorder. These disorders are often persistent, leading to significant emotional and financial burdens to patients, their family, and society at large. For many brain disorders, including depression, substance abuse, autism, schizophrenia, insomnia, and dementia, there is no cure. Available treatments address symptom relief and are only effective in subsets of patients. The World Economic Forum, the World Health Organization and the European Brain Council all urge for improved understanding of brain disorders. Problem definition: Most brain disorders have in common a so-called ‘complex’ aetiology: i.e., they are influenced by multiple genetic and environmental risk factors. Each factor contributes only a small proportion to the total disease risk, and each individual potentially carries a different combination of genetic risk factors. Recent genetic discovery studies provided unprecedented insight into the genetic architecture of brain disorders by revealing many of the genes involved. Despite this enormous success, these results have not translated into mechanistic insight. That is because the detected genetic effects are small and numerous, and their combined biological implications are unclear. This complex nature of brain disorders has so far seriously hampered mechanistic disease insight, a prerequisite for successfully developing treatments. Opportunity: Two major recent advancements are of high relevance: First, novel genomics’ technologies have led to large-scale initiatives that provide genetic and transcriptomic signature maps of the human brain, down to cellular resolution. These maps are radically changing our understanding of the brain, and contain enormous potential for the interpretation of the functional role of the hundreds of genes implicated in brain disorders, as they allow mapping of risk genes to cells via their cellular expression. Aligning results from genetic discovery studies with these novel cellular signature maps of the brain will translate genetic discoveries into actionable starting points for functional follow-up studies. Second, a recent revolution in tools and technologies in experimental neuroscience enables studying cells and circuitry with unprecedented resolution. These new precision tools facilitate rapid genome editing, targeted intervention of the activity of neurons in the brain and the study of human neurons derived from patient cells. They provide promising new avenues to functionally investigate the role of cells in circuitry and in causal relationships with disease-relevant behaviour. Taken together these recent advances provide unparalleled opportunities to gain mechanistic insight into specific brain (dys)function and lay a new foundation for designing innovative treatment options for brain disorders. Goal & Approach: Our primary goal is to gain insight into the molecular and cellular basis of complex brain disorders, by closely connecting genetics to neurobiology, facilitating new experimental approaches, and enabling the design of novel treatment strategies. First, we will develop algorithms to align results from genetic discovery studies with cellular signature maps of the brain and generate actionable hypotheses on the involvement of specific cell types (neurons and glia) in multiple brain disorders. Second, we will verify the involvement of these cell types in human and animal models relevant to selected brain disorders. Third, we will identify the neural circuitry in which identified cell types are involved. Fourth, we will determine the role of identified cell types and neural circuitry in behaviour relevant for the brain disorders. Fifth, at multiple stages of our project we will generate results that can potentially serve as starting points for novel treatment regimens – we will actively monitor this and push translation of our results. The project will build a computational and technological platform to translate genetic findings into mechanistic insights into brain disorders, so urgently needed. The consortium consists of 21 excellent researchers selected for their expertise representing the scientific fields that are crucial to meet the project’s goal. The project capitalizes on recent exciting advances in genetics and neurobiology and is highly timely; never before were the odds so much in favour of mechanistically understanding brain disorders. The BRAINSCAPE consortium is exceptionally well-positioned to successfully realize this unique opportunity.

Synaptic transmission provides the primary mode of communication of neurons in the brain. Synapses are small two-compartment (two-neuron) organelles containing a sender and receiver element in which ~2000 proteins are active to transduce signals and modulate the strength of transmission. In this application we request a mass spectrometer to enable a multi-year series of projects dedicated to investigate the synapse proteome regarding (i) cell-type and circuitry-specific synapse protein diversity, (ii) protein-protein interactions relevant for synapse function, (iii) synaptic plasticity in learning and memory formation and (iv) translational research on synapse-related neurological and psychiatric disorders (synaptopathies). The requested instrument (Thermo Orbitrap Exploris 480) specifically will allow us to measure comprehensive organellar proteomes and global protein posttranslational modifications at high sensitivity, addressing key frontier questions, that are not captured by current genomics studies. This instrument increases precursor ion selectivity by the use of an external ion mobility device, mitigates peptide co-elution problems for TMT multiplex samples analysis, improves the selection of chemical crosslinked peptides for protein-protein interaction studies, and has the possibility to use real-time mass-spec control through a programmable interface for optimized usage of MS measurement times. This MS is designed to have a high degree of robustness; 1000 samples can be analyzed with weekly simple maintenance service ensures constant and reproducible measurements that are mandated for large scale quantitative proteomics. Through this equipment innovation we can maintain forefront research at an internationally competitive level

Memory formation and its storage requires strengthening of connections between sparsely distributed neurons that are activated at the time of learning. In this project, researchers will causally pinpoint and connect the neurobiological processes that underlie and regulate this strengthening, in order to identify the precise synaptic code of successful memory formation.