# Mechanical compression induces neuronal apoptosis, reduces synaptic activity, and promotes glial neuroinflammation in mice and humans

## TL;DR

This study shows that mechanical compression from brain tumors causes neuron death, disrupts brain activity, and triggers inflammation in both mice and humans.

## Contribution

The study identifies specific pathways (HIF-1 and AP-1) activated by compression that could be targeted for neuroprotection in brain tumors.

## Key findings

- Chronic mechanical compression causes neuronal apoptosis and synaptic loss in neurons.
- Compression activates HIF-1 signaling and stress-adaptive genes in neurons.
- Glial cells show AP-1-driven gene expression and neuroinflammation in response to compression.

## Abstract

Glioblastoma, the deadliest primary brain tumor in adults, exerts physical forces on surrounding brain tissue, leading to neuronal damage. In the present study, by applying multiple model systems, we show that chronic 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, with reactive astrocytes contributing to the neuroinflammatory environment that accompanies neuronal loss. These findings reveal how compression exerted by space-occupying lesions may contribute to patients’ cognitive and motor impairments. This work lays the groundwork for therapies that protect neurons from mechanical injury, with relevance not only to glioblastoma but also to other neurological diseases that present with mass effect.

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, leading 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 multiscale compression systems and physiologically relevant in vitro and in vivo models, we find that chronic mechanical compression induces neuronal apoptosis and loss of synaptic puncta, leading to disrupted neural network activity, as assessed by calcium imaging. This is accompanied by increased HIF-1 signaling and upregulation of downstream stress-adaptive genes in neurons. We further show that chronic 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.