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

Abstract Tau pathology is a defining feature of Alzheimer’s disease (AD), yet the molecular factors that modulate its onset and progression remain incompletely understood. The proto-oncogene Src kinase, a non-receptor tyrosine kinase with broad roles in neuronal signaling, has been implicated in neurodegenerative processes, but its relationship to Tau pathology is not fully defined. We examined the spatial and molecular associations between Src and pathological Tau using immunohistochemistry, proteomics, and single-nucleus RNA sequencing in human postmortem brain tissue. Brownian dynamics simulations were performed to test whether Src interacts differentially with Tau conformations. Finally, we tested the effects of Src knockdown on Tau phosphorylation in PS19 transgenic mouse neurons. Src was significantly upregulated in multiple AD-associated brain regions and was highly expressed in vulnerable excitatory neurons. Network-based transcriptomic analysis identified NEUROD2 as a hub transcription factor within the Src-containing subnetwork, with both NEUROD2 and Src significantly upregulated in AD excitatory neurons, and NEUROD2 was validated by immunohistochemistry. Src strongly colocalized with early pathological Tau epitopes, most notably MC1. Mass spectrometry revealed increased phosphorylation of Src at Ser75, Tyr187, and Tyr439 in AD cases. Brownian dynamics simulations indicated a ~ 7-fold increase in Src–Tau contacts when Tau is in paired helical filament conformation compared to microtubule-bound Tau. Functionally, Src knockdown in PS19 hippocampal neurons reduced AT8-positivity. These data support Src as a molecular contributor to Tau pathology in AD, operating at early disease stages. While further studies are needed to establish causality in vivo, our findings highlight a potential NEUROD2–Src–Tau axis as a candidate pathway contributing to early pathology.