Authors
Li, H., Gross, E. R., Devine, A., Gundavelli, A., Prell, S. A., Woodbury, M. E., Gen, L., Doering, A., Held, A., Hyman, B. T., Serrano-Pozo, A., Zwang, T. J., Bennett, R. E., Das, S.
Abstract
Alzheimer's disease (AD) features widespread extracellular amyloid-{beta} plaques but selective intraneuronal tau accumulation in cortical layers II/III and V, while layer IV remains relatively resistant. Here, we combined subcellular spatial transcriptomics with co-registered A{beta} and pTau immunohistochemistry to determine why neurons exposed to comparable plaque-associated pathology differ in somatic pTau accumulation. Plaque-associated neuritic stress occurred similarly across layers, but layer IV neurons showed attenuated pTau accumulation and reduced somatic expression of a shared neurite-soma stress program involving DCTN1, CALM3, NORAD, and PIN1. Trajectory analysis within layers identified tau-vulnerable and resistant neuronal states implicating calcium signaling, retrograde transport, and lysosomal function. Notably, astrocytic APOE-neuronal LRP1 co-expression increased significantly along the pTau-vulnerable trajectory, and APOE {epsilon}4 was associated with stronger coupling of local plaque pathology to pTau-associated molecular programs. These findings reveal neuronal programs and neuron-glia interactions underlying selective tau vulnerability and resistance in AD, highlighting potential tau-targeting therapeutics.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Nov 2026.
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