Endoplasmic reticulum stress contributes to the decline in doublecortin expression in the immature neurons of mice with long-term obesity

Adult hippocampal neurogenesis (AHN) plays an important role in hippocampus-dependent function. The number of doublecortin (Dcx)-positive immature neurons in the dentate gyrus decreases over time, especially in the early stages of Alzheimer’s disease (AD), and is further reduced in later stages of AD. Obesity in midlife is associated with dementia later in life; however, the underlying mechanisms by which obesity results in the development of dementia later in life remain unknown. Here, we show that endoplasmic reticulum (ER) stress was activated in the hippocampus and processes of Dcx-expressing immature neurons were shortened, coexpressing CHOP in APP23 AD model mice with high-fat diet-induced long-term obesity and in aged Lepr(db/db) (db/db) mice. Moreover, in cells differentiating from hippocampal neurospheres, Dcx mRNA was rapidly degraded via a microRNA (miRNA) pathway after thapsigargin treatment in vitro. These results indicate that loss of Dcx mRNA induced by ER stress during AHN may cause memory impairment in obese individuals later in life.