IL-17A drives cognitive aging probably via inducing neuroinflammation and theta oscillation disruption in the hippocampus

Abstract

Cognitive aging is a major risk factor for neurodegenerative diseases and has a great impact on the living quality of older individuals. However, the precise mechanisms underlying cognitive aging remain elusive. Accumulating evidence has demonstrated that interleukin 17A (IL-17A) is responsible for cognitive decline in the process of various neurological diseases. Thus, we conducted this study aiming to investigate the role of IL-17A in cognitive aging. In the present study, 31 aging (65-85 years) and 25 young (18-35 years) patients scheduled for elective removal of internal fixation surgery with spinal anesthesia were included for measurements of preoperative cognitive function, serum and cerebrospinal fluid (CSF) levels of IL-17A. For animal study, RNAseq and Kyoto Encyclopedia of Genes and Genomes pathways were used to identify differentially expressed genes between young and aging mice. For the treatment groups, young (2-3 months) and aging (16-18 months) mice received intraperitoneally with IL-17A and anti-IL-17A antibody, respectively. Twenty-four hours later, neurocognitive behavioral tests were conducted. Our results suggested that differentially expressed genes between young and aging mice were mainly enriched in IL-17 pathways. Serum and CSF levels of IL-17A increased significantly in aging patients and were negatively correlated with mini-mental state examination scores. Both young mice receiving IL-17A and aging mice showed impaired memory, increased blood-brain barrier permeability, overactivated microglia and increased inflammatory mediators in the hippocampus. Additionally, aging mice showed a significantly decreased θ power in the task-related neural oscillations. Notably, intraperitoneal injection of anti-IL-17A antibody alleviated increased blood-brain barrier permeability, microglial activation, neuroinflammation, θ oscillation disruption and cognitive decline of aging mice. In conclusion, our study demonstrated that IL-17A may be an initiating factor of cognitive aging.

Keywords: Aging; Blood-brain barrier; Cognition; IL-17A; Neural oscillation.