XenoAD · Modelling the impact of aging in sporadic Alzheimer’s disease

Understanding therapeutic opportunities in Alzheimer’s disease (AD), the most common form of progressive neurodegeneration, is limited due to lack of animal models that replicate the disease’s consecutive stages. We achieved a breakthrough by xenografting human stem cell-derived neurons into mouse brains, where they integrate and survive up to two years, developing typical AD hallmarks. Neighbouring mouse neurons remain resilient to AD, underscoring unique human neuronal features not mirrored in rodents. Significant challenges persist, particularly modelling aging, the primary and most elusive risk factor for sporadic AD. The current model also lacks human microglia, crucial carriers of genetic risk for AD. We need to measure the impact of progressive disease on neuron function, as maintaining brain function is the ultimate goal. To address these challenges, we propose a novel method of transplanting human neurons that preserve their epigenetic markers of aging, together with human microglia in double xenografts. Concurrently, we will investigate neurons from healthy aging centenarians to understand the basis of AD resilience at old age. Our research tackles critical questions: (1) How do age-associated epigenetic changes modulate disease phenotype? (2) What is the molecular basis of resilience in centenarians? (3) Do newly discovered drug targets benefit neuronal function? (4) Which blood biomarkers track the effect of experimental treatments? This study focuses on human biology, using human cells, genes, and proteins, ensuring rapid translation to clinical settings. By the project’s end, we expect to identify at least four novel drug targets and their biomarkers, validated through preclinical studies. Developing the first animal models for sporadic AD is transformative for the field, allowing to map the molecular pathways in human neurons from health to degeneration. The work will lead to new therapeutics but may also lead to cell transplantation therapies for AD.