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Longitudinal Proteomic Profiling Defines a Two-Stage Remodeling Trajectory of Tauopathy in PS19 Mice

ABSTRACT: Tauopathies, including Alzheimer’s disease (AD), are characterized by progressive synaptic dysfunction, neuroinflammation, and neuronal loss. Across neuropathological and in vivo imaging studies, tau pathology shows a consistently tight relationship with cognitive impairment and neurodegeneration, often exceeding correlations observed for amyloid plaque burden, highlighting tau as a central determinant of clinical decline[1]. However, the temporal molecular transitions that connect early synaptic vulnerability to later inflammatory amplification and neurodegeneration remain incompletely defined. Here, we performed a longitudinal, label-free data-independent acquisition (DIA) proteomic profiling of brain tissues from PS19 (P301S) tau transgenic mice at 5, 6, and 7 months of age, together with 5-month noncarrier littermate controls. Comparative analysis at 5 months confirmed early tau-associated alterations involving synaptic organization, cytoskeletal regulation, and stress-responsive signaling pathways, consistent with prior reports that synapse loss and microglial activation can precede mature tau tangles in P301S/PS19-related models[2-5]. Furthermore, longitudinal profiling identified 776 significantly altered proteins (FDR < 0.05) that segregated into four distinct temporal expression patterns. These trajectories delineate a two-stage disease course, with an initial adaptive phase (5–6 months) marked by synaptic down-tuning and metabolic stress responses, followed by a transition toward an inflammatory and degenerative state (6–7 months). Notably, 6 months emerged as a molecular transition point characterized by coordinated activation of stress-associated signaling pathways. This transition timing is consistent with PS19/P301S literature indicating prominent neurofibrillary tangles (NFT) pathology around ~6 months with subsequent neurodegenerative escalation[6].

ORGANISM(S): Mus Sp.

SUBMITTER: Jiangjiang Zhu

PROVIDER: PXD075656 | iProX | Sun Mar 15 00:00:00 GMT 2026

REPOSITORIES: iProX

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Project description:Background: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer’s disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. Methods: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks. Results:Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks. Conclusion: This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insights into the molecular changes underlying microglia activation during tau mediated neurodegeneration.

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Longitudinal Proteomic Profiling Defines a Two-Stage Remodeling Trajectory of Tauopathy in PS19 Mice

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