Journal Article

Microglial AKAP8L: a key mediator in diabetes-associated cognitive impairment via autophagy inhibition and neuroinflammation triggering

Wang, Jian-hua, Wei, Qian-qian, Wang, Chang-shui, Zhang, Wen-yuan, Xie, Xin, Zhang, Tao, Chen, Jing, Jiang, Pei

2024

Overview

Background Diabetes-associated cognitive impairment (DACI) poses a significant challenge to the self-management of diabetes, markedly elevating the risk of adverse complications. A burgeoning body of evidence implicates microglia as a central player in the pathogenesis of DACI. Methods We utilized proteomics to identify potential biomarkers in high glucose (HG)-treated microglia, followed by gene knockdown techniques for mechanistic validation in vitro and in vivo. Results Our proteomic analysis identified a significant upregulation of AKAP8L in HG-treated microglia, with concurrent dysregulation of autophagy and inflammation markers, making AKAP8L a novel biomarker of interest. Notably, the accumulation of AKAP8L was specific to HG-treated microglia, with no observed changes in co-cultured astrocytes or neurons, a pattern that was mirrored in streptozotocin (STZ)-induced diabetic mice. Further studies through co-immunoprecipitation and proximity ligation assay indicated that the elevated AKAP8L in HG-treated microglial cells interacts with the mTORC1. In the STZ mouse model, we demonstrated that both AKAP8L knockdown and rapamycin treatment significantly enhanced cognitive function, as evidenced by improved performance in the Morris water maze, and reduced microglial activation. Moreover, these interventions effectively suppressed mTORC1 signaling, normalized autophagic flux, mitigated neuroinflammation, and decreased pyroptosis. Conclusions Our findings highlight the critical role of AKAP8L in the development of DACI. By interacting with mTORC1, AKAP8L appears to obstruct autophagic processes and initiate a cascade of neuroinflammatory responses. The identification of AKAP8L as a key mediator in DACI opens up new avenues for potential therapeutic interventions.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: A Kinase Anchor Proteins - genetics / A Kinase Anchor Proteins - metabolism / AKAP8L / Animals / Autophagy / Autophagy - drug effects / Autophagy - physiology / Biomedical and Life Sciences / Biomedicine / Cognition disorders / Cognitive Dysfunction - etiology / Cognitive Dysfunction - metabolism / Complications and side effects / Development and progression / Diabetes / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - metabolism / Diabetes-associated cognitive impairment / Immunology / Male / Mice / Mice, Inbred C57BL / Microglia / Microglia - metabolism / mTOR / Neurobiology / Neuroinflammation / Neuroinflammatory Diseases - metabolism / Neurology / Neurosciences / Risk factors