Redox-sensitive high mobility group box 1 (HMGB1) protein is a multipotent regulator in the pathogenesis of Alzheimer's disease

The primary cause of Alzheimer's disease (AD) is still unknown although genetic studies have identified several risk genes and significant alterations in the chromatin landscape. These genetic changes are associated with neuroinflammation and clear signs of neurodegeneration and cognitive impairment. While the redox-sensitive high mobility group box 1 (HMGB1) protein is a chromatin binding chaperone which maintains the integrity of chromatin, it is also a stress-induced alarmin factor released from the nucleus and subsequently secreted into extracellular space where it is a major inducer of inflammatory responses. There is abundant evidence that HMGB1 is a multifunctional regulator of AD pathology because it can (i) stimulate neuroinflammatory responses, (ii) disrupt the blood-brain barrier, (iii) inhibit microglial clearance of β-amyloid deposits, (iv) trigger cellular senescence and induce cell death, and (v) stimulate synapse loss and cognitive impairment. Experiments with transgenic AD mice have revealed that a release of HMGB1 from nuclei and its secretion promoted neuroinflammation and aggravated AD pathology. Conversely, it is known that the inhibition of HMGB1 expression or its nuclear release attenuated neuroinflammation and delayed the pathological changes in transgenic AD mice. Given that there are many drugs which can inhibit HMGB1-induced inflammatory states, it seems that HMGB1 is a promising therapeutic target to suppress AD pathogenesis.