Neurotoxic soluble amyloid-beta 42 (Aβ) oligomers are increasingly believed to cause synaptic failure in the hippocampus, leading to memory disability, in the early stages of Alzheimer's disease (AD). Hippocampal somatostatin (SST)-neprilysin (NEP) system is known to function as a defense system against the neurotoxic Aβ oligomers, and to be compromised due to aging and AD pathogenesis. Therefore, restoration of this compromised hippocampal SST-NEP system may enable prevention of onset of AD and progression of the illness. We originally found that nobiletin-rich Citrus reticulata peel also known as Nchinpi did prevent animal memory defect. Consistently, our pilot clinical study suggested its beneficial potential in patients with AD, without adverse side effects, including digestive symptom. In the present study in the hippocampus of aged mice as well as in primary cultures of hippocampus neurons, we therefore evaluated the impacts of Nchinpi extract on expression of SST and NEP genes. Treatment with Nchinpi extract did coordinately facilitate SST and NEP levels in the cultured neurons, as assayed by real-time RT-qPCR and ICC; and it raised mRNA levels for both genes tested in the hippocampus, when the Kampo medicine was orally given to aged (17-month-old) mice at a dose of 0.5 g/kg/day for 14 consecutive days. IHC uncovered the ability to raise neuronal SST- and NEP-immunoreactivities. These findings thus suggest that the Nchinpi extract highly likely prevents such an age-related decline in the hippocampal SST-NEP system's function.