Investigating Age Associated Neuronal Signaling in Glioblastoma

Document Type

Article

Publication Date

2026

JAX Location

JGM

Abstract

Recent studies reveal that glioblastoma (GBM) maintains its pervasiveness through neuron-glioma synapses which induces excitatory signaling. However, neurons are prone to degradation through natural aging and neurodegenerative diseases. Here, we investigate the intersection of aging and glioblastoma using single‑nucleus RNA‑sequencing (snRNA‑seq) data from a GL261 GBM model across young (3‑month), intermediate (12‑month), and old (22‑month) C57BL/6J mice. Sequencing data from paired brain hemispheres of each sample enabled direct within‑mouse comparisons to account for biological differences. We focused on glutamatergic neurons and microglia, performing unbiased gene set enrichment analysis followed by targeted pathway scoring of pseudobulk samples. We hypothesized that the older, tumor-bearing brain will exhibit worse neuronal degradation alongside higher microglial inflammation compared to its younger counterparts. We found that aging elevates inflammatory pathways in both cell types, while synaptic signaling pathways trend downward in glutamatergic neurons. The presence of the tumor also leads to upregulated inflammatory pathways in both cell types and suppression of synaptic signaling in glutamatergic neurons. The aged brain starts from a more inflamed and synaptically degraded baseline, however our data suggests that despite this, the impact of the tumor on synaptic signaling pathways is independent of age.

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