Src kinase emerges as a molecular player in early tau pathology in Alzheimer’s disease

Tau pathology is one of the defining hallmarks of Alzheimer’s disease, yet the molecular factors that influence when it begins and how it spreads remain incompletely understood. A new open-access study in Acta Neuropathologica Communications points to an unexpected participant: Src kinase, a non-receptor tyrosine kinase better known for its roles in cell signaling, which the authors identify as a candidate contributor to early tau pathology.

The research team, led by Diego Mastroeni and Benjamin P. Readhead with collaborators including Abhishek Singharoy, combined several complementary approaches. They examined human postmortem brain tissue using immunohistochemistry, proteomics and single-nucleus RNA sequencing to map the spatial and molecular relationships between Src and pathological tau. They then turned to computer simulations and, finally, to experiments in neurons from PS19 transgenic mice to test whether reducing Src affects tau phosphorylation.

The human tissue data showed that Src was significantly upregulated in multiple brain regions associated with Alzheimer’s disease. The kinase was also highly expressed in vulnerable excitatory neurons, the cell type that bears much of the burden of tau pathology in the disorder.

Network-based transcriptomic analysis added a regulatory dimension to the finding. It identified NEUROD2, a transcription factor, as a hub within the Src-containing subnetwork. Both NEUROD2 and Src were significantly upregulated in excitatory neurons from Alzheimer’s cases, and the NEUROD2 result was independently validated by immunohistochemistry, strengthening the case that this transcriptional program is genuinely altered in the disease.

At the protein level, Src strongly colocalized with early pathological tau epitopes, most notably MC1. Mass spectrometry further revealed increased phosphorylation of Src at three specific sites, Ser75, Tyr187 and Tyr439, in Alzheimer’s disease cases, suggesting that the kinase itself is modified in the diseased brain.

To probe the physical interaction between the two proteins, the researchers performed Brownian dynamics simulations. These indicated roughly a seven-fold increase in contacts between Src and tau when tau adopts the paired helical filament conformation compared with microtubule-bound tau. In other words, the pathological form of tau appears to interact far more extensively with Src than the normal, microtubule-associated form does.

When the researchers knocked down Src in hippocampal neurons from these animals, they observed a reduction in AT8-positivity. This result suggests that Src levels influence the phosphorylation state of tau in neurons, although it does not by itself establish causality in the human disease.

The authors are explicit about the limits of the work. The human data are associative, drawn from postmortem tissue, and the mouse experiment addresses one link in a longer chain of events. As they note, further studies are needed to establish causality in vivo before Src can be considered a confirmed driver rather than a correlate of tau pathology.

Even with those caveats, the study outlines a candidate pathway, a NEUROD2–Src–tau axis, that appears to operate at early disease stages.

Subject of Research: The role of Src kinase in early tau pathology in Alzheimer's disease

Article Title: Src kinase as a molecular contributor to tau pathology in Alzheimer’s disease

Article References: Mastroeni, D., Chan, C. K., Morshed, N., Diouf, D., de Ávila, C., Beirute-Herrera, J., Suazo, C., Nolz, J., Lopatin, U., Wang, Q., Serrano, G., Beach, T., Jensen, K., van den Hove, D., White, F. M., Chiu, P.-L., Reiman, E. M., Readhead, B. P., & Singharoy, A. (2026). Src kinase as a molecular contributor to tau pathology in Alzheimer’s disease. Acta Neuropathologica Communications. https://doi.org/10.1186/s40478-026-02444-2

Image Credits: AI Generated

DOI: 10.1186/s40478-026-02444-2

Keywords: Alzheimer's disease, tau pathology, Src kinase, NEUROD2, single-nucleus RNA sequencing, immunohistochemistry, phosphorylation, PS19 mice, Brownian dynamics, neurodegeneration, kinase, molecular