Challenge Workshop
October 11-15, 2026
Director: Bart De Strooper
UK Dementia Research Institute at University College London, London, UK & Katholieke Universiteit Leuven, Belgium
Co-Director: Pierre Magistretti
EPFL, École Polytechnique Fédérale de Lausanne, Switzerland
Faculty:
David Gate, Northwestern University Feinberg School of Medicine, Chicago, USA
Rosa Chiara Paolicelli, University of Lausanne, Switzerland
Jonathan Kipnis, Washington University in St. Louis, USA
Emanuela Pasciuto, University of Antwerp, Belgium
Soyon Hong, University College London, UK
Vijay Kumar Kuchroo, Harvard Medical School, Boston, USA
Pierre Magistretti, EPFL, École Polytechnique Fédérale de Lausanne, Switzerland
Bart De Strooper, UK Dementia Research Institute at University College London, London, UK & Katholieke Universiteit Leuven, Belgium
Immunity, inflammation, and energy metabolism are central to Alzheimer’s Disease, yet their roles shift dramatically over time and across brain regions. This Challenge Workshop, with world leaders in the field, asks when immune responses become maladaptive, where they operate within plaque and Tau-rich niches, and how microglia, astrocytes, and peripheral cells drive the transition from protection to pathology. Understanding these dynamics opens the door to interventions at the nexus of immunity, inflammation and energy metabolism that restore balance rather than suppress biology.
Bart De Strooper
Critical transitions that shape the development of Alzheimer’s disease
The course of Alzheimer’s disease is often portrayed as a simple progression in which amyloid beta deposition leads to Tau aggregation and, subsequently, to neuronal loss. An alternative view holds that the disorder advances through a series of biologically defined stages, separated by critical inflection points. At each threshold, accumulating stress exceeds the capacity of cellular systems to maintain equilibrium, resulting in abrupt, qualitative changes in cellular and circuit behaviour. The intervals between these inflection points can be understood as transition phases during which altered cellular states spread across anatomically and functionally distinct tissue domains. These domains form a patchwork that gradually involves vulnerable cognitive networks. Among these transitions, the onset of self-reinforcing Tau pathology represents a decisive turning point. By focusing on thresholds and timing rather than a linear cascade, this framework provides a coherent explanation for the frequent mismatch between pathological load and clinical symptoms. It also highlights the common structure underlying familial and sporadic forms of the disease and emphasises the slow erosion of homeostatic resilience as a defining feature of Alzheimer’s disease.
Vijay Kumar Kuchroo
Immune checkpoint molecules as guardians of microglial homeostasis and function
Among the cells that influence the course of Alzheimer’s disease (AD), microglia—which are the resident immune cells of the central nervous system (CNS)—play a pivotal role in sensing, engulfing, and removing pathological proteins, as well as regulating neuronal health. Since microglia often become dysfunctional and fail to clear toxic Aβ aggregates in AD, understanding the molecular pathways that restrain or activate microglial responses is central to developing new therapeutic strategies for AD.
One pathway that has recently emerged as a key regulator of immune cell activity is the immune checkpoint system. Immune checkpoints sustain immune balance by limiting activation in T cells and other immune subsets. The co-inhibitory receptor TIM-3 (T-cell immunoglobulin and mucin domain-3) is well established as a negative regulator of T cells, promoting exhaustion and impaired effector T cell responses1–3. TIM-3 blockade has become a major focus in cancer immunotherapy, with numerous clinical trials underway and TIM-3 is now recognized as an important regulator of myeloid cells, including macrophages and dendritic cells. Most relevant to AD, a recent genome-wide association study identified HAVCR2, the gene encoding TIM-3, as an AD susceptibility gene5. Intriguingly, within the CNS, TIM-3 expression is highly enriched in microglia, particularly as they mature into their homeostatic state. Microglia also co-express other checkpoint receptors, most notably LAG-3 (lymphocyte activation gene-3), but the functional significance of this co-expression in neurodegeneration has remained unexplored.
Our recent work revealed that TIM-3 is a central regulator of microglial homeostasis and function6. Selective deletion of Tim-3 in microglia converts them into a highly phagocytic, MGnD/DAM-like state without inducing inflammation, enabling more efficient clearance of Aβ plaques. In the 5xFAD AD model, microglia-specific Tim-3 deletion reduces neurotoxic plaque features and improves cognitive performance. Furthermore, TIM-3 and LAG-3 are enriched in non-phagocytic microglia, and Lag3 expression increases when Tim-3 is lost, suggesting compensatory or cooperative interactions between these checkpoint pathways6.
In aging mice, 5xFAD transgenic models, and human AD datasets, we observed concurrent upregulation of TIM3 and LAG3 in microglia, with TIM3⁺LAG3⁺ microglial populations correlating with AD neuropathologic change and dementia severity. In human APOE4 carriers (who have increased AD risk), TIM3/LAG3 double-positive microglia are particularly enriched. These findings collectively suggest that immune checkpoint receptors play a previously unrecognized role in regulating microglial function, and that dysregulated TIM-3 and LAG-3 signalling may contribute to AD pathogenesis. Together, these observations point to a crucial immunoregulatory axis in AD involving TIM-3 and LAG-3 and will be a focus of discussion during the talks.
Jonathan Kipnis
Brain clearance as a key factor in neuroimmunology
Recent evidence has challenged many dogmas in neuroimmunology. Brain-derived ‘waste’ from deep within the brain is mobilized via the glymphatic system towards immunologically active brain borders, where meningeal lymphatic vessels are appropriately positioned to drain waste and antigens from the brain to the periphery. The presentation of brain-derived self-peptides at the brain’s borders is critical for enabling active immunosurveillance, limiting aberrant immune reactivity, and clearing the brain of toxic compounds. Taking these novel concepts into account, we develop new therapies for neurodegenerative diseases, including lymphatic-based modifications such as genetic, pharmacological and surgical approaches.
David Gate
Immune contributions to Alzheimer’s disease pathogenesis and therapy
The immune system plays a dynamic and complex role in Alzheimer’s disease (AD), with protective and pathological contributions that evolve across disease stages. My laboratory investigates how adaptive and innate immune mechanisms intersect with neurodegeneration, focusing on T cell responses, microglial states, and their therapeutic modulation. Previously, we demonstrated that clonally expanded CD8 T cells patrol the cerebrospinal fluid (CSF) in AD patients, revealing an adaptive immune response characterized by antigen-driven clonal expansions that may influence neuroinflammation. Building on this, subsequent studies revealed CSF immune dysregulation during healthy brain aging and cognitive impairment, showing that CSF immune cells change with age and in AD, with shifts in T cell and myeloid populations that disrupt brain homeostasis. Furthermore, epigenetic dysregulation in peripheral immunity in AD was shown, highlighting chromatin accessibility changes in circulating immune cells (particularly CD8 T cells and monocytes) that are linked to genetic risk factors such as ApoE and promote inflammatory gene expression. More recent studies have also identified microglial mechanisms driving amyloid-β clearance in immunized AD patients. Using spatial transcriptomics on brain tissue from clinical trial participants, we showed that effective amyloid removal is associated with specific microglial phenotypes that not only clear plaques but also help restore a healthier brain environment. Current research in the lab is exploring immune mechanisms in cerebral amyloid angiopathy (CAA)-related inflammation. We are applying single-cell and spatial transcriptomic approaches to dissect the interplay between microglia, vascular pathology, and peripheral immune infiltration in CAA, aiming to identify molecular drivers of inflammation and potential targets for mitigating vascular complications in AD. This work underscores the importance of timing, context, and cellular states in harnessing immunity for AD therapy.
Emanuela Pasciuto
Microglia-T cell crosstalk in Alzheimer’s disease: from cellular mechanisms to therapeutic implications
Alzheimer’s disease is often viewed through the lens of amyloid beta accumulation, Tau pathology, and neuronal dysfunction. However, disease progression is also shaped by immune transitions that alter how the brain responds to pathology over time. Microglia are central to this process, but their function is not determined by intrinsic programs alone. Increasing evidence suggests that adaptive immune cells, particularly T cells, enter the Alzheimer’s disease brain and may influence whether microglial responses remain protective, become ineffective, or contribute to tissue damage. Microglia–T cell crosstalk acts as a regulatory axis in Alzheimer’s disease, and the timing of immune activation and early microglial priming shapes later responses to amyloid pathology. In preclinical models, we find increased infiltration of both CD4-positive and CD8-positive T cells in the Alzheimer’s disease brain, together with a relationship between T cell accumulation and major histocompatibility complex class II expression on microglia. These observations support the idea that antigen presentation marks a disease-associated immune state in which microglia become positioned to communicate with adaptive immune cells.
Using genetic models that selectively remove major histocompatibility complex class II from microglia, we further examine whether this pathway is required for T cell recruitment, microglial functional state, and plaque-associated responses.
The therapeutic relevance of this interaction is particularly important, as several immune-based approaches now aim to harness protective regulatory T cell responses in neurodegenerative disease. Building on this concept, the talk will discuss regulatory T cell-based strategies and their effects on microglial function in preclinical models of Alzheimer’s disease. Brain-directed interleukin-2 treatment modifies microglial phenotype, induces major histocompatibility complex class II expression, enhances microglial phagocytic capacity, and alters disease-related microglial transcriptional programs without broadly inducing inflammatory modules. These findings suggest that regulatory T cells may influence Alzheimer’s disease progression, at least in part, by reshaping microglial responses to amyloid pathology.
Together, these data support a model in which microglia–T cell interactions are active regulators of disease progression rather than secondary consequences of neurodegeneration. Defining when these interactions promote resilience or dysfunction may help refine immune-based therapeutic strategies for Alzheimer’s disease and other neurodegenerative disorders marked by chronic inflammation and antigen presentation.
Soyon Hong
Neuroimmune control of synapse vulnerability in neurodegeneration
My laboratory investigates how neuroimmune pathways shape selective synaptic and neuronal vulnerability in neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Rather than viewing inflammation as a uniform downstream response to pathology, we study how microglia, astrocytes, border-associated macrophages, and peripheral immune cells detect and interpret early changes in neuronal activity, proteostasis, and tissue state. I will discuss our work on immune-mediated synapse loss, including complement- and phagocytosis-related mechanisms, astrocyte–microglia signalling, and brain-border macrophage pathways that modulate microglial function and cognitive decline. Together, these studies support a model in which age-related synaptic dysfunction reflects a progressive failure of immune and glial homeostatic capacity across vulnerable neural interfaces. Understanding when these responses are protective, compensatory, or maladaptive may reveal therapeutic windows for restoring neuroimmune balance before irreversible circuit damage occurs.
Rosa Chiara Paolicelli
Early-life microglial dysfunction in the pathogenesis of brain disease
Microglia play essential roles in both brain physiology and pathology. It is now well established that a large proportion of genetic variants associated with an increased risk of neurodegenerative disorders are highly enriched in microglia, strongly suggesting that microglial dysfunction contributes to susceptibility to neurodegeneration. However, the precise mechanisms and developmental stages through which these risk genes influence microglial behavior and promote brain pathology remain poorly understood.
Notably, several microglia-associated risk genes implicated in neurodegenerative disorders are not only expressed under pathological conditions but are also highly enriched during brain development. This observation raises the intriguing possibility that genetic risk variants may critically influence microglia during sensitive developmental windows, thereby affecting the mechanisms by which these cells shape neural circuit formation and maturation, as well as myelin integrity.
It is reasonable to hypothesize that the mechanisms by which microglial dysfunction confers vulnerability to brain disease should be investigated well before disease onset. By combining in vivo mouse models with ex vivo and in vitro approaches, our laboratory investigates how impaired microglial function influences brain development, leading to long-lasting alterations in neuronal function and behavior, and how disease-associated risk genes contribute to these processes. In this context, we highlight the importance of critical developmental windows and propose that microglial dysfunction during early postnatal development may be a key determinant of increased susceptibility to neurodegeneration later in life.
Pierre Magistretti
Neuron–glia metabolic coupling mediated by lactate: relevance for neuroenergetics, neuroplasticity and neurodegenerative diseases
A tight metabolic coupling between astrocytes and neurons is a central feature of brain energy metabolism. Over the years, my lab has identified and molecularly characterised two key mechanisms of neurometabolic coupling: neuromodulator (VIP, adenosine and noradrenaline)-induced glycogenolysis in astrocytes and glutamate-stimulated aerobic glycolysis. Both processes lead to the release of lactate from astrocytes, which serves as an energy substrate for neurons as defined by the Astrocyte-Neuron Lactate Shuttle (ANLS) model.
Subsequent work in my lab showed that lactate also acts as a signalling molecule, enhancing NMDA receptor activity, promoting long-term memory, and activating gene expression programs linked to synaptic plasticity. Electrophysiological and behavioural studies further demonstrated that astrocytic lactate supply is activity-dependent and scales with computational demand. Recent data indicate that lactate potentiates NMDAR currents via monocarboxylate transporter (MCT)-dependent neuronal uptake, conversion to pyruvate, increased NADH, and redox-sensitive modulation of GluN2B subunits, involving CaMKII signalling.
Recent preclinical studies in various conditions show that pharmacological stimulation of the ANLS restores behavioural deficits present in hypometabolic conditions such as Glut1 deficiency syndrome (de Vivo disease) and Alzheimer’s disease, supporting the strategy of targeting astrocytes to overcome brain hypometabolism. In preclinical models of depression, lactate was shown to exert antidepressant effects that depend on neurogenesis. Together, these findings establish lactate as a metabolic–signalling nexus linking astrocyte function to neuronal computation, plasticity, and behaviour, and open new therapeutic perspectives for neurodegenerative, mood, and metabolic brain disorders.