Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans
Mass effect, characterized by the compression and deformation of neural tissue from space-occupying lesions, can lead to debilitating neurological symptoms and poses a significant clinical challenge. In the primary brain tumor glioblastoma (GBM), we have shown previously that compressive solid stress originating from the growing tumor reduces cerebral blood flow, leads to neuronal loss, increased functional impairment, and poor clinical outcomes. However, the direct effects of compression on neurons and the underlying biophysical mechanisms are poorly understood. Here, using multi-scale compression systems and physiologically relevant in vitro and in vivo models, we find that mechanical compression induces neuronal apoptosis and synapse loss, leading to disrupted neural network activity. This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons. We further show that compression triggers AP-1-driven gene expression in glial cells, promoting a neuroinflammatory response. Together, these findings reveal that solid stress directly contributes to neuronal dysfunction and inflammation caused by GBM by activating distinct pathways that can be targeted in future studies for neuroprotection. SIGNIFICANCE STATEMENTGlioblastoma (GBM), the deadliest primary brain tumor in adults, exerts physical forces on surrounding brain tissue as it grows, leading to neuronal damage. However, the molecular mechanisms underlying this process are not well understood. In the present study, by applying multiple model systems, we show that mechanical compression triggers neuronal apoptosis, disrupts synaptic communication between neurons, and reduces neural network activity. We also find that compression activates inflammatory pathways in both neurons and glia, further contributing to neuronal damage. These findings reveal how compression exerted by space-occupying lesions may contribute to patients cognitive and motor impairments and suggest new directions for treatment. This work lays the groundwork for therapies that protect neurons from mechanical injury, with relevance not only to GBM but also other neurological diseases that present with mass effect.