To distinguish age-related memory loss more explicitly from Alzheimer’s disease (AD)

To distinguish age-related memory loss more explicitly from Alzheimer’s disease (AD) we have explored its molecular underpinning in the dentate gyrus (DG) a subregion of the hippocampal formation thought to be targeted Troxacitabine by aging. in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits much like those associated with aging as measured by novel object acknowledgement and Morris water maze assessments. Functional magnetic resonance imaging studies showed that within the hippocampal formation dysfunction was selectively observed in the DG and this corresponded to a regionally selective decrease in histone acetylation. Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together these findings show that this DG is usually a hippocampal subregion targeted by aging and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention. INTRODUCTION The hippocampal formation a circuit made up of interconnected subregions plays a vital role in memory. Each hippocampal subregion houses a populace of neurons with unique molecular expression profiles and physiological properties. This molecular and functional anatomy is usually thought to account in part for the differential vulnerability of hippocampal subregions to numerous pathogenic mechanisms (1). Indeed although both Alzheimer’s disease (AD) and the normal aging process impact hippocampal-dependent memory processes several recent studies suggest that the two disorders might be distinguished by unique anatomical patterns of hippocampal dysfunction (1). Postmortem studies have suggested that this entorhinal cortex (EC) as well as the CA1 subregion and the subiculum are the hippocampal subregions that are most affected by AD (2 3 whereas the dentate gyrus (DG) and CA3 are relatively preserved (2 4 5 Comparable patterns have been detected in vivo by high-resolution variants of functional magnetic resonance imaging (fMRI) (6-8). In contrast to AD normal aging does not cause cell death or other pathognomonic histological abnormalities. Rather age-related memory loss is usually characterized by dysfunctional neurons and therefore functional endpoints are best suited for mapping age-related hippocampal dysfunction. Results from high-resolution fMRI (7 9 10 and cognitive studies (11-14) suggest that the primary initial target of normal aging is the DG Tead4 whereas the EC is usually relatively preserved (1). Although these anatomical patterns are suggestive no specific molecular defects underlying age-related DG dysfunction have been identified. To obtain more direct evidence that age-related memory loss is not an early form of AD we sought to isolate a molecular correlate of the aging human DG and explore whether this molecule mediates age-related memory loss. We hoped that these experiments could accomplish two goals. First the results could confirm or deny the anatomical pattern associated with aging and therefore further establish that aging and AD target the hippocampal circuit via individual mechanisms. Second these findings could offer insight into the etiology of age-related memory loss with the potential of opening up new therapeutic avenues. Although well suited to Troxacitabine screen for molecular correlates of aging gene expression profiling presents analytic difficulties when applied to tissue harvested from postmortem human brain. Unlike the controlled experimental Troxacitabine setting of animal models the many genetic and life-style differences between human subjects affect expression levels independent of age and are therefore considered sources of variance. As explained (15) one Troxacitabine approach to addressing this challenge is usually to normalize expression levels to a region unaffected by aging thereby reducing sources of variance. Guided by the image studies examined above we used expression levels in the EC to normalize expression in the DG. In so doing we recognized 17 candidate aging-associated genes and focused on one RbAp48 whose decline in expression best correlated with the aging human DG. We then turned to mouse models and used cognitive fMRI and molecular analyses to examine the role.