Work performed:
Completed polygenic risk score analyses and generated > 20 iPSC lines from donors with high or low AD polygenic risk.
Developed and applied isogenic lines to isolate genetic effects.
Established CRISPR Cas9 capacity and generated loss of function lines for key risk genes.
Established and validated human microglial and astrocyte xenograft models.
Implemented single cell transcriptomic profiling of transplanted cells across disease contexts.
Developed a pooled xenotransplantation or village approach enabling analysis of multiple donor lines in the same brain and computational donor assignment.
Data generation and computational analysis:
Generated and analysed > 300,000 human microglial and > 50,000 astrocyte single cell transcriptomes.
Developed robust pipelines for single-cell/nucleus analysis, cellular state identification, transition mapping, pathway analysis, and polygenic risk stratification.
Applied spatial transcriptomics to map gene programs within pathological niches and to infer cell-cell interaction networks.
Therapeutic and mechanistic testing:
Tested microglial effector programs for antibody-mediated amyloid clearance using lecanemab.
Established human neuron xenograft workflows to assess amyloid-induced tau pathology, biomarker release, and neuronal loss.
Identified and tested a pharmacologically targetable neuronal death pathway linked to tau pathology.
Roles of microglia and astrocytes:
Demonstrated that APOE isoforms shape transcriptional and epigenomic programs in human microglia exposed to amyloid pathology in vivo.
Identified effects of PICALM loss on microglial identity and microglia-amyloid interactions.
Showed that microglia contribute to plaque seeding in early states, while compacting them and limiting neuritic damage in later states.
Demonstrated that astrocytic APOE can restore amyloid pathology and trigger microglial responses in Apoe-deficient mice.
Established that antibody-mediated amyloid clearance requires an intact Fc, functional microglia, and a microglial effector program.
Mapped microglia–astroglia networks around plaques via spatial transcriptomics, supporting a cellular AD phase.
Human neuron vulnerability and neuronal death:
Demonstrated that human neurons xenografted into amyloid bearing mouse brains develop tau pathology, release p-tau into the blood, and undergo neuronal loss.
Identified a granulovacuolar degeneration-associated necroptosis program as a driver of neuronal loss and showed pharmacological rescue.
Exploitation and dissemination:
Disseminated results through high-impact publications such as Cell, Nat Neurosc, Nat Comm, EMBO Mol Med, and Science Transl Med, and an invited Science review.
Released and shared methodologies, including xenograft protocols and computational pipelines, adopted by multiple laboratories.
Contributed to Tech Transfer and exploitation through company formation: results led to the creation of K5, now part of Muna Therapeutics, to translate spatially resolved molecular insights into therapeutic strategies.
Provided training and knowledge transfer through the development of researchers who progressed to independent positions and through collaborations with academic and industry partners.
