N-myc downstream-regulated gene 2 deficiency aggravates memory impairment in Alzheimer's disease

•The protein levels of NDRG2 in the hippocampus of AD mice were increased with the development of AD.•NDRG2 deficiency worsened memory impairment in AD mice.•NDRG2 deletion induced downregulation of the proteasome functional subunit PSMB6 in AD mice. Alzheimer's disease (AD) is a chronic degenerative disease of the central nervous system and the most common dementia type in elderly people. N-myc downstream-regulated gene 2 (NDRG2), a cell stress response gene, is primarily expressed in astrocytes in mammalian brains. The hippocampal protein levels of NDRG2 in AD patients were significantly higher than those in healthy peers. However, whether the increase in NDRG2 is involved in the development of AD or is an endogenous protective response initiated by stress remains unknown. Here, we investigated the roles of NDRG2 in the development of memory impairment in AD using mouse models established by amyloid β injection or crossing of APP/PS1 mice. We found that NDRG2 deficiency worsened the memory impairment in AD mice. In addition, NDRG2 deletion induced downregulation of the proteasome functional subunit PSMB6 in AD mice. These findings suggest that NDRG2 is an endogenous neuroprotectant that participates in the pathological course of waste-clearing impairment and memory damage in AD. NDRG2 may be a therapeutic target for the intervention of AD memory degradation.