Background:

Repetitive mild traumatic brain injury (rmTBI) is a recognized risk factor for later-life neurodegeneration, yet the stress-response mechanisms that regulate tau pathology and glial reactivity after repeated injury remain poorly defined. Endoplasmic reticulum (ER) stress signaling, mediated in part by protein kinase RNA-like ER kinase (PERK), has been implicated in tau dysregulation and neuroinflammatory processes. Whether PERK deficiency increases molecular and network vulnerability to rmTBI is unknown.

Methods: 

Using 14-month-old PERK knockdown mice, we examined the molecular, functional, and structural consequences of rmTBI. Spatial proteomics and targeted immunohistological analyses quantified tau-related, neurodegeneration-associated, and glial markers across brain regions. These molecular data were integrated with resting-state functional MRI collected 5 days post-injury to assess functional connectivity and regional network strength, with a focus on hippocampal circuitry following rmTBI.

Results: 

PERK deficiency markedly amplified rmTBI-induced accumulation of pathological tau species (phospho-tau S214, S396, S404) and increased glial activation markers (Iba1 and GFAP). In parallel, neurodegeneration-associated proteins (APP, PSEN1, and α-synuclein) were elevated, indicating enhanced proteostatic stress in PERK-deficient mice. Molecular alterations were regionally concentrated in hippocampal and cortical network hubs and overlapped with disrupted functional connectivity specifically in PERK-deficient animals exposed to rmTBI. Spatial alignment of molecular and imaging findings revealed that heightened tau and glial stress responses tracked with increased vulnerability of large-scale brain networks following repetitive injury.

Conclusion: 

These findings demonstrate that PERK deficiency exacerbates tau pathology, glial reactivity, and network disruption after repetitive mild brain injury. By linking ER stress dysregulation to molecular and systems-level vulnerability, this work provides mechanistic insight into how rmTBI may accelerate neurodegenerative trajectories and identifies ER stress pathways as potential targets for mitigating dementia risk after repetitive injury.