Cognitive impairment due to Alzheimer’s disease, and memory loss that occurs simply as we grow older, seem to stem from deficiencies in different areas of the hippocampus. Now, research published in the August 28 Science Translational Medicine identifies a molecule responsible for slowing “normal aging” in particular. It is the histone-binding protein RbAp48. Brain levels of this protein appear to drop with age, and researchers at Columbia University Medical Center, New York, showed they could boost cognition in old mice, or induce deficits in young mice, by dialing expression of RbAp48 up or down in the brain, respectively. The findings could pave the way for developing better diagnostics and interventions for age-related memory decline, said Scott Small, who co-led the study with Columbia colleague Eric Kandel.
In postmortem human brain, AD pathology ravages the entorhinal cortex and spares the dentate gyrus of the hippocampus (Braak et al., 2006; Gómez-Isla et al., 1996; Thal et al., 2002), whereas Small’s functional magnetic resonance imaging (fMRI) research suggests the opposite pattern of neuronal dysfunction in normal aging (see ARF related news story; see also Small et al., 2002 and Small et al., 2004). To date, there was no molecular support for the idea that AD and age-related memory loss target different hippocampal regions.
In search of molecular differences, first author Elias Pavlopoulos and colleagues used microarrays to identify genes that might rise or fall with age in the dentate gyrus—the brain region most heavily implicated in normal aging—but not in the entorhinal cortex. They collected tissue from disease-free postmortem brains of eight people who had died between the ages of 33 to 88. First the researchers normalized expression of dentate gyrus genes to that in entorhinal cortex, then they correlated the normalized transcripts with the person’s age. The analysis yielded 17 hits—eight genes whose expression was higher in older dentate gyrus, and nine whose expression was lower.
The transcriptional regulator RbAp48, a gene in the latter group, showed the most robust age-related loss in expression. RbAp48 promotes expression of other genes by interacting with c-AMP response element binding protein (CREB) proteins to encourage histone acetylation (Zhang et al., 2000), which is critical to maintain cognitive function (see ARF related news story). In a separate set of 10 postmortem brains from normal controls ranging in age from 41 to 89 years, RbAp48 mRNA and protein levels were lower in dentate gyrus, but not entorhinal cortex or other hippocampal areas of older people, confirming the microarray data.
To determine if RbAp48 changes affect cognition, Pavlopoulos and colleagues generated mice expressing an inducible dominant-negative RbAp48 (RbAp48-DN) in the forebrain. Feeding the animals doxycycline inhibited RbAp48-DN expression, whereas switching to doxycycline-free chow allowed it. “We asked if we could inhibit RbAp48 function in a young mouse and make it look cognitively like an old mouse,” Small told Alzforum. The answer was yes, the scientists report.
In novel object recognition and spatial memory tests, 3.5-month-old RbAp48-DN mice—in which RbAp48 was expressed from birth but turned off for a 40-day period before testing—performed as poorly as 15-month-old wild-type animals. The young RbAp48-DN mice showed fMRI abnormalities in the dentate gyrus, as well as reduced acetylation of histone H4, which has been linked to age-dependent memory loss (see ARF related news story). These changes did not appear in other hippocampal regions. In the converse experiment, old mice performed like young after lentiviruses boosted their RbAp48 levels in the dentate gyrus by 67 percent (see image below).
Upregulating RbAp48 (yellow) in the dentate gyrus of old mice restores their memory back to that of young mice. Image credit: Elias Pavlopoulos, Columbia University Medical Center
Steve Haggarty of Massachusetts General Hospital, Boston, considers the study “a tour de force effort” integrating functional genomics with mouse analyses to pinpoint a molecule that appears to play a role in age-dependent memory loss (see comment below). The findings add to growing evidence linking epigenetic modifications to memory loss in normal aging and neurodegenerative disease. Loss of the transcriptional regulator could suppress histone acetylation, much as an overly exuberant histone deacetylase might. HDAC2 has been shown to suppress memory in mice (see ARF related news story), and selectively inhibiting this gene restores cognition in an AD mouse model (see ARF related news story). Scientists have identified small molecules that inhibit HDAC activity (see Fass et al., 2013; ARF conference story), and EnVivo Pharmaceuticals of Watertown, Massachusetts, has moved a brain-penetrant HDAC inhibitor through Phase 1 (see company news release).
To what extent the HDAC2 pathway associated with memory loss in AD mice dovetails with the RbAp48 mechanism implicated in normal aging remains unclear. The pathways overlap “insofar as both RbAp48 and HDAC2 affect CREB/CBP-mediated gene expression and likely other forms of chromatin-mediated neuroplasticity,” Haggarty notes. However, “whether RbAp48 interacts with the HDAC2 complex in the context of the hippocampus remains to be understood,” he wrote.—Esther Landhuis