Spatial Single Cell Characterization of Alzheimer's Disease in Mouse and Human Hippocampus

Alzheimer’s disease is the most common cause of dementia and the seventh leading cause of death in the United States. The accumulation of protein aggregates (i.e., extracellular Aβ plaques and intracellular tau-containing neurofibrillary tangles) constitute the biological hallmarks of Alzheimer’s disease. Clinical trials enhancing the clearance of Aβ and tau have failed to alter disease progression indicating disease complexity beyond protein accumulation. Comprehending the cellular and molecular features of cells and their environments in Alzheimer’s disease is urgently needed to develop effective disease modifying therapies. To uncover interactions between cells containing tau pathology and their microenvironments, Dr. Orr’s team employed NanoString GeoMx® Digital Spatial Profiling (DSP). They performed a spatial-proteomic analysis of postmortem brains from individuals with Alzheimer’s disease neuropathology with or without dementia. Comparing the protein expression profiles in neurons and their microenvironments led to identification of molecules differentially regulated in individuals resilient to dementia, despite the presence of neuropathology. To gain mechanistic insights into the role of tau pathogenesis her team utilized CosMx^TM Spatial Molecular Imaging. Their spatial-transcriptomic analysis comparing a mouse model of tau neuropathology to an age-matched control identified cellular population changes with spatially-resolved gene expression differences across 42 cell types. The analyses further revealed a tau-dependent loss of three cellular niches involving neuronal, glia and vascular cells.

 

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