RBAP48 Drives Age-Related Memory Loss

RESEARCH HIGHLIGHTS

MEMORY RBAP48 drives age-related memory loss

As the population ages, there is a are the regions most affected by indicate that lack of RBAP48 com- pressing need to understand the Alzheimer’s disease and that the DG promises the ability of young mice to lack of mechanisms underlying age-related is relatively unaffected. By contrast, form robust memories of novel objects forgetfulness. However, given that both imaging and cognitive studies and locations and recapitulates the RBAP48 neurodegenerative diseases also lead indicate that normal ageing primar- cognitive defects that are characteristic compromises to memory impairments, it has been ily affects neurons in the DG. To of hippocampal ageing. the ability of difficult to distinguish between the molecularly characterize the ageing RBAP48 is known to interact with young mice to effects of diseases such as Alzheimer’s hippocampus and shed light on the histones and modify histone acetyla- and those of normal ageing on mechanisms underlying age-related tion, which is crucial for memory form robust hippocampal-dependent memory memory loss, the authors carried out consolidation. In the RBAP48-DN memories of processes. By focusing on age-related an extensive gene expression study in expressing mice, a DG-specific novel objects changes in the dentate gyrus (DG), post-mortem DG and EC tissue from decrease of the histone acetyltrans- and locations a subregion of the hippocampus eight human brains, ranging in age ferase (HAT) activity of CREB-binding thought to be targeted by ageing, from 33 to 88 years. They used the protein (CBP) and a reduction in the Pavlopoulos et al. show that the expression levels in the EC to nor- levels of acetylated histones H4 and loss of the histone-binding protein malize expression in the DG and thus H2B were observed. Interestingly, RBAP48 (also known as RBBP4) is identify 17 ageing-associated genes. when the authors increased RBAP48 key to age-related memory decline. The gene that manifested the expression in the DG of aged mice Previous studies have suggested most significant decline with age was through lentiviral gene transfer, that the entorhinal cortex (EC) and RBAP48, so the authors explored its they were not only able to improve the CA1 region of the hippocampus function further in mice. Consistent the mice’s memory deficits but also with their findings in humans, the increase the HAT activity of CBP and levels of RBAP48 were lower in the the levels of acetylated H4 and H2B. DG of aged mice than in young mice. In summary, this study suggests Furthermore, when the expression of a that the distinct anatomical patterns forebrain-specific, dominant negative of hippocampal dysfunction may form of RBAP48 (RBAP48-DN) was be used to distinguish the effects of induced in young mice, their perfor- ageing and Alzheimer’s disease on mance in a novel-object recognition memory and that RBAP48 is a key memory task and a spatial memory driver of age-related memory loss. The task was worse than that of their con- development of agents that increase trol siblings. In both tasks, the mem- signalling through CBP might be ory deficits observed were similar to useful to reduce age-related memory those of aged wild-type mice with a impairments. similar genetic background. When Monica Hoyos Flight

the authors stopped the expression ORIGINAL RESEARCH PAPER Pavlopoulos, E. of RBAP48-DN by feeding the mice et al. Molecular mechanism for age-related doxycycline, they were able to reverse memory loss: the histone-binding protein RbAp48. Sci. Transl. Med. 5, 200ra115 (2013) DIGITALVISION the effects. Together, these findings

NATURE REVIEWS | NEUROSCIENCE VOLUME 14 | OCTOBER 2013