Monoaminergic changes are associated with impaired neurogenesis along the longitudinal axis of the hippocampus in ageing and dementia

Abstract

Neurogenesis persists in the adult human hippocampus and is thought to support memory and emotional regulation. Both normal ageing and Parkinson disease dementia (PDD) are associated with reduced hippocampal neurogenesis, but why this occurs and how this might change across the across the hippocampal axis remains unclear. Here, we quantified the expression of genes regulating neurogenesis from stem cell production to neuron maturation and examined their relationship with monoaminergic activity throughout the post-mortem hippocampus in young and aged individuals, as well as in individuals with PDD. DCX and MKI67 expression were markedly reduced in PDD cases throughout the hippocampus, while GFAP and GFAP{delta} were elevated in aged control individuals but not in PDD. Dopamine and serotonin levels were unchanged but reduced levels of the dopamine metabolite DOPAC, and increased levels of the serotonin metabolite 5-HIAA, were present across the hippocampal axis in PDD. Hierarchical regression analysis identified DOPAC and 5-HIAA as significant predictors of DCX and MKI67 expression independent of diagnostic group. Coupling between stem cell markers and proliferative output was preserved in the hippocampus of young controls but was absent in aged controls and in PDD. These data suggest changes in monoaminergic systems are linked to stage-specific deficits in neuronal proliferation and maturation, identifying a potential mechanistic bridge to cognitive decline in PDD.