Key Mediator Akap8l in Microglia for Diabetes-Associated Cognitive Impairment: Functions via Autophagy Inhibition and Neuroinflammation

Academic Background

In recent years, diabetes-associated cognitive impairment (DACI) has received increasing attention. It not only poses a threat to the self-management capabilities of diabetic patients but also increases the risk of adverse complications. Previous studies have shown that microglia play a central role in the pathogenesis of DACI. The aim of this study is to reveal the developmental pathways of DACI and possible intervention measures.

Source of the Paper

The study was conducted collaboratively by researchers from multiple Chinese academic institutions and scientific research institutes, including WenYuan Zhang, QianQian Wei, Tao Zhang, Changshui Wang, Jing Chen, Jianhua Wang, Xin Xie, and Pei Jiang. The paper was published on page 177 of volume 21 of the Journal of Neuroinflammation in 2024, with Pei Jiang (jiangpeicsu@sina.com) as the contact for correspondence. Participating institutions include Zhongshan People’s Hospital, Zunyi Medical University, Jining First People’s Hospital, Jining Medical Research Institute, Hospital Affiliated to Jining Medical University, Key Laboratory of Neurobiology of Jining Medical University, and Warwick Medical School of University of Warwick, UK.

Research Workflow and Main Findings

The study identified potential biomarkers in microglia treated with high glucose (HG) using proteomics, and subsequently validated the potential mechanisms via in vitro and in vivo gene knockout techniques. The study found a significant upregulation of Akap8l in microglia treated with HG, along with the disorder of autophagy and inflammation markers, making Akap8l a new biomarker of interest. The accumulation of Akap8l was specific to microglia treated with HG, and a similar pattern was observed in streptozotocin (STZ)-induced diabetic mice. Further studies showed that the upregulated Akap8l interacted with mTORC1 in microglia treated with HG. In the STZ mouse model, researchers demonstrated that Akap8l gene knockout and Rapamycin treatment significantly improved cognitive function and reduced the activation of microglia. These interventions effectively inhibited mTORC1 signaling, restored autophagic flux, alleviated neuroinflammation, and reduced pyroptosis.

Conclusions and Significance

Through its interaction with mTORC1, Akap8l appears to hinder the autophagy process and trigger a series of neuroinflammatory responses. Akap8l, revealed as a key mediator of DACI, opens new avenues for potential therapeutic interventions. The scientific value of this research lies in enhancing our understanding of DACI and its associated molecular mechanisms and provides potential targets for future therapeutic research.

Highlights of the Study

This research increases the understanding of issues within the field of research on diabetes-associated brain damage. The innovation lies in the identification of a new biomarker, Akap8l, related to the inflammatory state of microglia using proteomics technology, and through multilevel verification experiments, revealing its function in diabetes-associated cognitive impairment and its potential therapeutic significance, providing new strategies for intervention in diabetes-related complications.