High Mobility Group Box 1 Ameliorates Cognitive Impairment in the 3×Tg-AD Mouse Model

Alzheimer's disease (AD) is the most common cause of dementia. Studies indicate that neuroinflammation plays an important role in the pathophysiology of AD. High-mobility group box 1 (HMGB1) is an important chromatin protein. It can be secreted by immune cells and passively released from damaged cells to promote inflammation. HMGB1 also can recruit stem cells and promote their proliferation and tissue repairing. However, the role of HMGB1 in the progression of AD is currently unknown.

The aims were to investigate the effect of HMGB1 on the AD-related pathologies and cognitive function using 3×Tg-AD mouse model.

Female 5-month-old 3×Tg-AD mice were intracerebroventricularly injected with 4.5 μg of HMGB1 or with saline as a control. The levels of interesting protein were assessed by western blots or immunofluorescence. The effect of HMGB1 on the cognitive function was evaluated by one-trial novel object recognition test and Morris water maze.

Intracerebroventricular injection of recombinant HMGB1 ameliorated cognitive impairment in 5-6-month-old 3×Tg-AD mice. The levels of synapsin 1, synaptophysin, MAP2, NeuN, and phosphorylated CREB were increased in HMGB1-treated 3×Tg-AD mouse brains. HMGB1 decreased intracellular amyloid-β level but did not affect tau phosphorylation. HMGB1 treatment also promoted neurogenesis in the dentate gyrus and increased the level of GFAP in the 3×Tg-AD mouse brains.

These results reveal a novel function of HMGB1 in enhancing neuroplasticity and improving cognitive function in 3×Tg-AD mice.