Intercellular signaling and synaptic deconstruction uncovered by single-cell and spatial transcriptomics in an AD tauopathy model

Topic: Brain proteins, microglia and lab models

Alzheimer’s disease (AD) is the leading cause of dementia in elderly individuals worldwide; however, all mechanisms leading to disease onset and progression are not well understood. Here, we report brain single-cell multiome and spatial transcriptomics in a transgenic rat model of human-like tauopathy. We have identified new markers of tau-driven AD pathology and provided single-cell evidence for genes implicated in AD. Our findings reveal how tau hyperphosphorylation and aging alter ligand-receptor communication, transcription factor regulatory networks, and specific cellular networks. Notably, we found intriguing changes in cell communication involving glutamatergic transmission and Netrin signaling as a taupathy consequence. Overall, this study reinforces the concept that synaptic dysfunction is a critical early event in AD and highlights potential targets as potential therapeutic strategies. Single-cell multiome and spatial transcriptomic analysis reveals new disease markers in the hippocampus implicated in both early and late stage of a tauopathy model of Alzheimer’s Disease.

Key findings

• Our findings reveal how tau hyperphosphorylation and aging alter ligand-receptor communication, transcription factor regulatory networks, and specific cellular networks.
• Notably, we found intriguing changes in cell communication involving glutamatergic transmission and Netrin signaling as a taupathy consequence.
• Overall, this study reinforces the concept that synaptic dysfunction is a critical early event in AD and highlights potential targets as potential therapeutic strategies.

Why it matters

In a transgenic rat model of human-like tauopathy, single-cell and spatial transcriptomics revealed changes in cell communication involving glutamatergic transmission and Netrin signaling. The study reinforces that synaptic dysfunction is an early event and highlights potential targets, but it is animal model work.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s42003-025-08959-z
• PubMed: 41249845
• Original source →
• Free full text: Communications Biology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{ji2025-41249845,
  author  = {Ji, Jeff X. and Giles, Brian L. and Bhattacharjee, Surjyadipta and Kautzmann, Marie-Audrey Ines and Masson, Alasdair P. and Carmo, Sonia Do and Cuello, A. Claudio and Bazan, Nicolas Guillermo},
  title   = {{Intercellular signaling and synaptic deconstruction uncovered by single-cell and spatial transcriptomics in an AD tauopathy model}},
  journal = {Communications Biology},
  year    = {2025},
  doi     = {10.1038/s42003-025-08959-z},
  pmid    = {41249845},
  url     = {https://doi.org/10.1038/s42003-025-08959-z}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Sex differences in Alzheimer's disease and common neuropathologies of aging Acta neuropathologica · 2018-10-17 · usefulness score 70/100 · Brain tissue and pathology
• Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau Journal of neuropathology and experimental neurology · 1999-06-01 · usefulness score 52/100 · Lewy body dementia
• NEBULA is a fast negative binomial mixed model for differential or co-expression analysis of large-scale multi-subject single-cell data Communications biology · 2021-05-26 · usefulness score 52/100 · TREM2 and immune genetics
• Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production Cell death and differentiation · 2009-01-16 · usefulness score 46/100 · Risk genes beyond APOE

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• Cell-mediated neuroprotection in a mouse model of human tauopathy The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-07-01 · usefulness score 36/100
• High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model Aging cell · 2016-01-19 · usefulness score 40/100

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