Graphical summary of data collection and acquisition. Cropped from Foiani et al., 2026. “Spatial single-cell proteomics reveals molecular trajectories of tangle-bearing neurons in Alzheimer’s disease.“ bioRxiv (2026). doi: https://doi.org/10.64898/2026.04.26.720932; Licensed under the terms of the Creative Commons CC-BY 4.0 license.

Alzheimer’s disease (AD) is characterised by the accumulation of amyloid-β plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. While NFT burden correlates with cognitive decline, a key gap in the field has been understanding the molecular consequences of tangle formation at the level of individual neurons — particularly given that neighbouring neurons within the same brain region can be differentially affected.

To address this, researchers applied exploratory, data-independent acquisition (DIA)-based spatial proteomics to individual neurons laser-microdissected from archival FFPE human AD brain tissue. Neurons were stratified by phospho-tau (pTau) status and profiled either as single cells or small pools, enabling both depth of coverage and single-neuron resolution. Samples were separated on an Aurora® Elite™ 15×75 CSI C18 UHPLC column coupled to an Evosep One, with data acquired on a timsTOF Ultra 2 in dia-PASEF mode.

Using this workflow, the researchers demonstrated that tangle-bearing neurons do not simply activate cell-death programmes but instead undergo a staged, adaptive molecular response to rising tau burden. An early shift away from proteasome-mediated degradation toward lysosomal proteolysis was identified, alongside a progressive decline in synaptic machinery. Critically, pTau-negative neurons from the same brain region already displayed molecular changes associated with early disease trajectory, suggesting that pathological remodelling precedes overt tau accumulation.

These findings challenge binary classifications of affected versus unaffected neurons and open new avenues for therapeutic intervention targeting early proteostasis disruption before irreversible neuronal damage occurs.

Publication
bioRxiv

Authors

M.S. Foiani, M. Bourdenx, L. Kraller, R.S. Nirujogi, A. Yiu, H. Davies, S. Patel, L.S. Damoc, L. Mitchener, Z. Jaunmuktane, F. Coscia, & K.E. Duff;

Title

Spatial single-cell proteomics reveals molecular trajectories of tangle-bearing neurons in Alzheimer’s disease