Cell-type specific profiling of human entorhinal cortex at the onset of Alzheimer’s disease neuropathology [scRNA-seq]

Neurons located in the layer II of the entorhinal cortex (ECII) are the primary site of pathological tau accumulation and neurodegeneration at preclinical stages of Alzheimer's disease (AD). Exploring the alterations that underlie the early degeneration of these cells is essential to develop therapies that delay disease onset. Here we performed cell–type specific profiling of the EC at the onset of human AD neuropathology. We identify an early response to amyloid pathology by microglia and oligodendrocytes. More importantly, we find that the Reelin signaling pathway is already impaired at this early disease stage, particularly in ECII neurons. This indicates that dysregulation of this pathway, with emerging genetic association with AD, plays a pivotal role in the selective vulnerability of the EC and in the onset of AD neuropathology. Study of the gene expression changes undergone by EC cells at the onset of AD neuropathology; we compare human postmortem EC without (control C1 to C5) or with incipient AD neuropathology or ADN (AD1 to AD5). All individuals were asymptomatic at death. Two samples C5 and AD1 were used for cell clustering but not for differential expression analysis because their amyloid levels did not correspond to their respective groups. For excitatory neurons, processed data correspond to our nuclei integrated with nuclei from Leng et al, Nature Neuro, 2021 to increase nucleus counts.