DECODING NEUROIMMUNITY WITH SPATIAL MULTIOMICS IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles, synaptic dysfunction, and neuronal loss, ultimately leading to cognitive decline (PMID: 33986301). Nowadays, detailed mapping and characterization of the complex interplay between Aβ deposits and neuroinflammation in AD pathogenesis remains challenging.
This study integrates multiplexed immunofluorescence and RNA in situ hybridization to map the cellular and molecular interplay between neurodegeneration and the neuroimmune landscape in an AD mouse model.
Bain sections of an APP-PS1 transgenic mouse (PMID: 19936202) were stained and imaged on the fully automated COMET™ platform, combining RNAscope™ (PMID: 22166544) HiPlex Pro and sequential immunofluorescence (seqIF™, PMID: 37813886) protocols. Multiomics image analysis was done using the HORIZON™ software.
Multiplex protein panels enabled precise mapping of Aβ protein aggregates, neighboring cell populations, and their interactions in situ. Complementary RNA panels targeted genes involved in neuroinflammation responses and neuronal signaling. Integration of protein and RNA targets into the newly developed multiomics assay enabled comprehensive profiling of cell-specific responses around Aβ plaques, revealing coordinated alterations in immune activation and neuronal function. Spatial tissue analysis further identified local recruitment of reactive astrocytes and microglia to areas containing extracellular Aβ plaques. These glial cells exhibited a signature consistent with a pro-inflammatory phenotype, underscoring their role in AD pathophysiology. 
This fully automated multiomics approach enables high-resolution spatial profiling of the cellular environment surrounding neurodegenerative lesions, providing new opportunities to explore the complex spatial and molecular interactions at the interface between neurodegeneration and neuroimmunity.