Stein-O’Brien, Genevieve L.Palaganas, RyanMeyer, Ernest M.Redding-Ochoa, JavierPletnikova, OlgaGuo, HaidanBell, William R.Troncoso, Juan C.Huganir, Richard L.Morris, Meaghan2025-05-132025-05-132025Stein-O'Brien GL, Palaganas R, Meyer EM, et al. Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer's disease. Cell Rep. 2025;44(3):115422. doi:10.1016/j.celrep.2025.115422https://hdl.handle.net/1805/48065In primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated in disease overall but up-regulated in tau-pathology-positive neurons. Two transcriptional signatures were associated with intraneuronal tau, both validated in a cortical AD dataset. Genes in the up-regulated signature were enriched in calcium regulation and synaptic function. Notably, transcriptional changes associated with intraneuronal tau in PART and AD were similar, suggesting a possible mechanistic relationship. These findings highlight the power of molecular analysis stratified by pathology and provide insight into common pathways associated with tau pathology in PART and AD.en-USPublisher PolicyAlzheimer’s diseaseNeuroscienceNeurodegenerationNeurofibrillary tanglesPrimary age-related tauopathyTauTranscriptionArticle