Discovery of the Immune Checkpoint as a Potential Regulator of Neuroinflammation in Alzheimer's Disease via Proteomics Approach

초록

Alzheimer's disease (AD) is a neurodegenerative disease, and the leading cause identified so far is an accumulation of abnormally folded β-amyloid. However, there was less improvement when targeting only β-amyloid. Not only β-amyloid but also inflammatory molecules such as IL-1β and TNF-α were increased in the post-mortem brains of patients. Chronic neuroinflammation, one of the pathophysiologies of AD, has been revealed to play a critical role in the progression and pathogenesis of AD. Targeting neuroinflammation is on the rise as a new therapeutic target. Immune checkpoints (ICPs), which are remarkable targets for cancer therapy, could also serve as new regulators of neuroinflammation. In this study, we aimed to investigate the role of ICPs as potential therapeutics in AD. To discover molecular characteristics related to the neuroinflammation of AD, we used 5xFAD mice. Through quantitative proteomics and subsequent data science studies, we identified changes in signal modules associated with inflammation. Furthermore, we discovered that a specific ICP exhibited abnormal expression in the cortex and hippocampus of 5xFAD through Western blotting and qPCR. Then, we checked the expression of ICP in the in vitro model mimicking neuroinflammation. The treatment using ICPs may offer a new perspective on therapeutic methods in AD.