Abstract: Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease. Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease. Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease. However, the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood. Recently, regulator of G protein signaling 6 (RGS6) was identified as the mediator of voluntary running–induced adult hippocampal neurogenesis in mice. Here, we generated novel RGS6fl/fl; APPSWE mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running–induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model. We found that voluntary running in APPSWE mice restored their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells, which also abolished running-mediated increases in adult hippocampal neurogenesis. Adult hippocampal neurogenesis was reduced in sedentary APPSWE mice versus control mice, with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells. RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons. Thus, RGS6 mediated voluntary running–induced rescue of impaired cognition and adult hippocampal neurogenesis in APPSWE mice, identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.

Key words: adult hippocampal neurogenesis,  , Alzheimer’s disease,  , dentate gyrus,  , exercise,  , learning/memory,  , neural precursor cells,  , regulator of G protein signaling 6 (RGS6)