ApoE4 increases susceptibility to stress-induced age-dependent depression-like behavior and cognitive impairment

Though apolipoprotein E ε4 (APOE ε4) is a major genetic risk factor for late-onset Alzheimer's disease, its association with depression remains controversial. In present study, 3-month-old and 8-month-old apoE-targeted replacement (TR) mice were both subjected to chronic unpredictable mild stress (CUMS) for six weeks. The results showed that 8-month apoE4-TR mice were more susceptible to the CUMS-induced depression-like behaviors and cognitive impairment than age-matched apoE3-TR mice. Stress induced a loss of GABAergic neurons and decline of Reelin level in the prefrontal cortex (PFC) and in the dentate gyrus (DG) of the hippocampus in both 3-month-old and 8-month-old apoE-TR mice, which were more pronounced in the 8-month-old apoE4-TR mice. Of note, stress decreased the level of PSD95 in the hippocampal synaptosome and increased the phosphorylation of N-methyl-D-aspartate receptor subunit GluN2B in the hippocampus of 8-month-old apoE4-TR mice. However, the expressions of apoE and apoE receptor 2 (apoER2) were not affected by stress. The study provides rodent evidence that APOE ε4 may increase the risk of depression and dementia in the elderly population by impairing the GABAergic signaling pathway and enhancing the GluN2B phosphorylation, which signifies that GluN2B inhibitors in clinical settings may be effective for elderly depression patients with APOE4 carriers.