Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex
- 1Rosalind Franklin Institute
Abstract
More neurons die in Alzheimer's disease than form tangles, and tangle-bearing neurons can persist for decades, so tangles alone cannot explain degeneration. We combined 6,000-plex spatial transcriptomics with PHF1 immunofluorescence (167,176 cells; 9 donors) and imaging mass cytometry (170,195 cells; 62 donors), measuring each cell's distance to the nearest tangle. Tangle-bearing layer 2-3 excitatory neurons were enriched late along a trajectory of increasing microtubule-associated, synaptic and V-ATPase expression, with elevated p62 and K48-ubiquitin. Tangle-free neurons shared more of this state the closer they lay to a tangle, including higher chaperone and autophagy scores, p62 and nuclear size. Nearby glia had higher disease-associated scores, with astrocytes expressing less GFAP. Excitatory, but not inhibitory, neuron loss was greatest in subtypes closest to tangles and cortical depths richest in phosphorylated tau. Selective neuronal vulnerability may reflect not only a neuron's susceptibility to forming a tangle but also where it lies relative to one.
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BibTeX
@misc{boulger2026neuronal,
title = {{Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex}},
author = {S. L. Boulger and N. Lambie and J. Wos and M. Papageorgopoulou and S. Mendez Pastor and E. Adair and M. Thomas and A. Caramello and N. N. Fancy and J. S. Jackson and E. P. Duff and A. Mallach and P. M. Matthews},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762234},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762234v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex
AU - S. L. Boulger
AU - N. Lambie
AU - J. Wos
AU - M. Papageorgopoulou
AU - S. Mendez Pastor
AU - E. Adair
AU - M. Thomas
AU - A. Caramello
AU - N. N. Fancy
AU - J. S. Jackson
AU - E. P. Duff
AU - A. Mallach
AU - P. M. Matthews
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762234
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762234v1
AB - More neurons die in Alzheimer's disease than form tangles, and tangle-bearing neurons can persist for decades, so tangles alone cannot explain degeneration. We combined 6,000-plex spatial transcriptomics with PHF1 immunofluorescence (167,176 cells; 9 donors) and imaging mass cytometry (170,195 cells; 62 donors), measuring each cell's distance to the nearest tangle. Tangle-bearing layer 2-3 excitatory neurons were enriched late along a trajectory of increasing microtubule-associated, synaptic and V-ATPase expression, with elevated p62 and K48-ubiquitin. Tangle-free neurons shared more of this state the closer they lay to a tangle, including higher chaperone and autophagy scores, p62 and nuclear size. Nearby glia had higher disease-associated scores, with astrocytes expressing less GFAP. Excitatory, but not inhibitory, neuron loss was greatest in subtypes closest to tangles and cortical depths richest in phosphorylated tau. Selective neuronal vulnerability may reflect not only a neuron's susceptibility to forming a tangle but also where it lies relative to one.
ER -