Insulin‐like growth factor‐I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in female aging rats

Abstract

In rats, learning and memory performance decline during aging, which makes this rodent species a suitable model to evaluate therapeutic strategies of potential value for correcting age-related cognitive deficits. Some of these strategies involve neurotrophic factors like insulin-like growth factor-I (IGF-I), a powerful neuroprotective molecule in the brain. Here, we implemented 18-day long intracerebroventricular (ICV) IGF-I gene therapy in 28 months old Sprague-Dawley female rats, and assessed spatial memory performance in the Barnes maze. We also studied hippocampal morphology using an unbiased stereological approach. Adenovectors expressing the gene for rat IGF-I or the reporter DsRed were used. Cerebrospinal fluid (CSF) samples were taken and IGF-I levels determined by radioimmunoassay. At the end of the study, IGF-I levels in the CSF were significantly higher in the experimental group than in the DsRed controls. After treatment, the IGF-I group showed a significant improvement in spatial memory accuracy as compared with DsRed counterparts. In the dentate gyrus (DG) of the hippocampus, the IGF-I group showed a higher number of immature neurons than the DsRed controls. The treatment increased hippocampal astrocyte branching and reduced their number in the hippocampal stratum radiatum. We conclude that the ependymal route is an effective approach to increase CSF levels of IGF-I and that this strategy improves the accuracy of spatial memory in aging rats. The favorable effect of the treatment on DG neurogenesis and astrocyte branching in the stratum radiatum may contribute to improving memory performance in aging rats.

Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline

“…Each cell type involved in neurovascular coupling (i.e. neurons, astrocytes, endothelial cells) are known targets of IGF-1 (Pardo et al 2016; Sonntag et al 2013) and there is good reason to believe that circulating IGF-1 deficiency is an important contributing factor to neurovascular dysfunction in aging. In endothelial cells IGF-1 was shown to regulate ROS production, mitochondrial oxidative stress, NO bioavailability and antioxidant response pathways (Bailey-Downs et al 2012; Csiszar et al 2008).…”

Daily supplementation with GrandFusion® improves memory and learning in aged rats

“…Since these changes contribute to the aging process, anti-aging therapies have mostly failed to prevent the evolution of aging into chronic aging. Therefore, the best approach for aging should be capable of limiting neuronal loss, oxidative stress, inflammation and abnormal neurogenesis [47-50]. In this context, complexes and drugs having neuroprotective and/or anti-aging properties are excellent for preventing age-induced chronic neuronal dysfunction typified by aging, cognitive and mood impairments.…”

Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging

“…34 It is of interest that IGF-I gene therapy in old female rats also increased hippocampal astrocyte branching and reduced their numbers in the hippocampal stratum radiatum. 31 In an earlier study, an age-related reduction in length and complexity of hippocampal astrocyte processes in female rats was reported. 28 Reduced branching in aged astrocytes may impair the ability of these cells to provide trophic support to neurons.…”

“…30 This way it was possible to efficiently transduce the ependymal layer, thus increasing CSF levels of IGF-I in old female rats even 18 d after vector injection. 31 With this approach it was observed that IGF-I gene therapy significantly improved spatial memory accuracy as compared with control counterparts. In the DG of the old rats submitted to IGF-I gene therapy it was observed a higher number of immature neurons than in the old controls.…”

“…In the DG of the old rats submitted to IGF-I gene therapy it was observed a higher number of immature neurons than in the old controls. Since IGF-I gene therapy increases the neurogenic activity in the DG of old rats 31 an increased neurogenesis may induce an improvement of pattern separation, which is defined as the ability to separate the components of memories into distinct complex memory representations that are unique and therefore allow an accurate discrimination of similar patterns. The DG is thought to be the main hippocampal structure involved in pattern separation memory 32 and the level of neurogenesis in the DG is directly related to pattern separation performance in rodents.…”