D-galactose Induced Brain Aging Mechanism

Objectives: Chronic injection of D-galactose can cause a progressive deterioration in learning and memory capacity and serve as an animal model of aging. The aim of this study was to evaluate the potential of this model for studying brain aging, and to investigate whether astrocytes are invloved in this model.Methods: The adult rats were injected with D-galactose for 6 weeks, and then behavioral tests were performed to quantify their abilities for exploration, learning, and memory. Immunohistochemistry for choline acetyltransferase and acetylcholinesterase histochemistry were performed to analyze cholinergic neurons in the basal forebrain and cholinergic terminals in the hippocampus respectively. Synaptic degeneration in the hippocampus was observed by electron microscopy. To investigate the involvement of astrocytes in this model, oxidative stress biomarkers, biochemical and pathological changes of astrocytes including astrocyte-derived nitric oxide, were examined in the hippocampus of the rats, following six weeks D-galactose injection.Results: D-galactose-injected rats displayed substantial impairments in open-field and water-maze performance, relative to saline-injected rats. The histopathological results showed that D-galactose-treated rats had decreases in the amount of cholinergic terminals in the hippocampus and in numbers of cholinergic soma both in the medial septum and the nucleus of the vertical limb of the diagonal band of Broca. Ultrastructural analysis confirmed major synaptic degeneration in the hippocampus following D-galactose injection. Furthermore, D-galactose-injected rats exhibited substantial impairment of the antioxidant systems and a significant increase in nitric oxide levels and a decrease in glutathione levels. Consistent with these biochemical changes, pathological changes of astrocytes were observed at both light and electron microscopic levels. Discussion: These findings suggest impairment of septohippocampal cholinergic system may contribute to deficits in learning and memory induced by long-term injection of D-galactose. Moreover, impairments of astrocytes are involved in oxidative stress-induced brain aging by chronic injection of D-galactose.