Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex

A new study reveals that neuronal and glial transcriptional states vary depending on their proximity to tangle-bearing neurons in the human entorhinal cortex. Alzheimer's disease is characterized by more neurons dying than forming tangles, and tangle-bearing neurons can persist for decades, rendering tangles alone an insufficient explanation for degeneration.

To investigate this phenomenon, the researchers employed 6,000-plex spatial transcriptomics, PHF1 immunofluorescence, and imaging mass cytometry on 167,176 cells from 9 donors and 170,195 cells from 62 donors, respectively. This allowed them to measure the distance of each cell to the nearest tangle and assess its expression levels of various molecular markers.

The study found that tangle-bearing layer 2-3 excitatory neurons exhibited an enrichment of late-stage expression of microtubule-associated, synaptic, and V-ATPase proteins, alongside elevated p62 and K48-ubiquitin levels. Interestingly, tangle-free neurons shared more of the same state but only when they were closer to a tangle, displaying higher chaperone and autophagy scores, increased p62, and larger nuclear size.

Additionally, nearby glial cells, particularly astrocytes, displayed higher disease-associated scores, with reduced GFAP expression. The research also highlighted that excitatory neurons, but not inhibitory ones, experienced the most significant loss in subtypes closest to tangles and in cortical depths with greater phosphorylated tau levels.

Ultimately, the study suggests that selective neuronal vulnerability in Alzheimer's disease may result from a combination of a neuron's inherent susceptibility to forming a tangle and its spatial relationship to tangle-bearing neurons.