# Loss of AMPK potentiates inflammation by activating the infammasome in a preclinical mouse model of TBI

## TL;DR

This study shows that loss of AMPK after traumatic brain injury worsens inflammation and brain damage in mice, suggesting that restoring AMPK activity could be a new treatment strategy.

## Contribution

The study identifies AMPKα1 as a key regulator of neuroinflammation and tissue damage after TBI, offering a novel therapeutic target.

## Key findings

- AMPK loss after TBI correlates with worsened behavioral deficits and increased NLRP3 inflammasome activation.
- AMPKα1-KO glial cells show heightened inflammatory responses compared to wild-type cells.
- Restoring AMPKα1 activity may help reduce neuroinflammation and brain injury damage.

## Abstract

Traumatic brain injury (TBI) is a major cause of mortality and long-term neurological disabilities. Adenosine monophosphate-activated protein kinase (AMPK), a key cellular energy sensor, plays a critical role in maintaining energy homeostasis. Loss of AMPK phosphorylation following TBI impairs the restoration of cellular energy homeostasis and promotes inflammation. In this study, we investigated whether post-TBI loss of AMPK worsens functional impairments, amplifies inflammation, and exacerbates tissue damage in a mouse model of TBI.

Adult male C57BL/6 wild-type (WT) and (AMPKα1-KO) mice were subjected to TBI or sham surgery. Behavioral assessments were performed at 24 h post-TBI, followed by mice were anesthetized, and their brains were rapidly collected for histological and biochemical analyses. To further support our findings, mixed glial cells isolated from WT and AMPKα1-KO pups were treated with lipopolysaccharides and interferon-gamma (LI) (0.1 μg/ml LPS and 20 ng/ml IFNg) for 6 h to induce an inflammatory response.

Our results show that TBI reduces AMPK phosphorylation in WT mice and that AMPK loss correlates with worsened behavioral deficits, enhanced NLRP3 inflammasome activation, and elevated levels of pro-inflammatory mediators, including IL-1β. Similarly, AMPKα1-KO glial cells exhibited greater activation of NLRP3 inflammasome and higher expression of pro-inflammatory markers, such as IL-1β, IL-6, TNF-α, iNOS, and Cox 2, compared with WT cells.

Collectively, our results demonstrate that AMPKα1 is a critical endogenous regulator of glial-driven neuroinflammation and secondary tissue damage following TBI. Restoring AMPKα1 activity after TBI may therefore represent a promising therapeutic strategy to attenuate neuroinflammation and limit TBI-associated neurological damage.