Progranulin Enhances Memory in Normal Aging and Alzheimer's Disease Mice

Abstract

Progranulin is a lysosomal and secreted protein that has neurotrophic properties and promotes neurite outgrowth in vitro. Mutations in the progranulin gene have been found to cause frontotemporal dementia. Additionally, reduced progranulin levels may be a risk factor for the development of Alzheimer's disease (AD). Studies in mouse models of AD support this notion: reducing progranulin exacerbates disease progression whereas increasing progranulin confers protection. However, the physiologic function of progranulin in the CNS is not known. We tested the effects of CNS-administered progranulin in the cognition in young male CD-1 mice, (3-months of age), old C57/BL male mice (24 months of age), 3xTG-AD male and female mice (13 months of age) and SAMP8 mice (12 months of age). Immediately following T maze foot shock avoidance training, CD-1 mice (n = 10 per group) were injected intracerebroventricularly (ICV) with progranulin (0, 0.005, 0.1 or 1.0 ug/2 ul). C57/BL 24 month old (n= 8~9/group) and the 13 month old 3xTG-AD mice (n = 8~9/group), were given either 0 or 1.0 ug/2 ul immediately after training. The 12 month old SAMP8 mice (n = 10~11/group) were given 0, 0.1 or 1.0 ug/2ul. Retention was assessed one week after training. The number of trails to reach a criterion of 5 avoidances in 6 consecutive trails was determined. Following behavioral testing, cortex, hippocampus, and plasma were harvested. CD-1 mice that received and an ICV injection of progranulin 0.1 and 1.0 ug/2 ul had significantly improved retention in T-maze than the mice which receive vehicle. These mice took significantly fewer trials to make an avoidance than the mice which received 0 ug/2 ul. Progranulin at 1.0 ug/2 ul improved retention in the 24 month old C57/BL mice, the 13 month old 3xTG-AD mice Progranulin at 0.1 and 1.0 ug/2ul improve retention in the 12 month old SAMP8 mice. It is becoming increasingly apparent that progranulin is involved in memory dysfunction. We found that progranulin has a direct influence on memory consolidation as its administration following foot shock avoidance training leads to improved memory retention. Our studies suggest that progranulin can directly modulate memory in both cognitively normal and AD mice, indicating that is has an important role not only in the pathogenesis of frontotemporal dementia, but in normal aged-related cognitive decline and AD progression as well.