30 Aug 2013

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

Comments

1. • Steve Haggerty
     
   • Posted: 01 Sep 2013
   • Paper: Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48.

   This elegant study by Kandel and colleagues represents a tour-de-force effort to integrate functional genomic studies spanning human post-mortem brain gene expression analysis to mouse models to uncover an important molecule involved in chromatin-mediated neuroplasticity. One that appears to play a key role in age-dependent memory loss.

   What is exciting about this study is that it not only builds on the Kandel, and other laboratories', previous work on the role of CREB/CBP-mediated transcription in memory formation, but it also nicely complements recent findings that have pointed to a key role for the family of zinc-dependent histone deacetylases (HDACs), particularly HDAC2, as memory suppressors that are involved in normal learning and memory and also in neurodegeneration.

   Excitingly, pharmacological inhibitors of this family of HDACs, such our recently described compound crebinostat (Fass et al., 2013), can enhance the transcription of CREB-CBP targeted genes through removing repressive chromatin-modifying activities leading to improved memory in mice. Similarly, selective targeting of HDAC2 with RNAi in the hippocampus can restore memory and the expression of key genes for synaptic plasticity in the context of Alzheimer's disease-like mouse models (Graff et al., 2012). Based upon these findings, drugs selectively targeting HDACs to overcome the loss of RBAP48 may be beneficial for normal age-dependent memory loss in addition to neurodegeneration.

   Additionally, as emphasized by this study on RBAP48, as alternatives to targeting HDACs, the discovery of other pharmacological agents targeting CREB/CBP-mediated transcription, for example through enhancing the acetyltransferase activity of CBP or blocking other components of the co-repressor complexes that antagonize CBP-mediated histone acetylation, may provide new avenues to enhance memory and prevent age-dependent memory loss in normal individuals and in the context of the degenerating brain. Future studies aiming to elucidate the detailed molecular mechanisms through which RBAP48 modulates chromatin-mediated neuroplasticity will hopeful guide such efforts in the near future.

   References:

   Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao WN, Nieland TJ, Guan JS, Kuhnle CE, Tang W, Barker DD, Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ. Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology. 2013 Jan;64:81-96. Epub 2012 Jul 4 PubMed.

   Gräff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM, Nieland TJ, Fass DM, Kao PF, Kahn M, Su SC, Samiei A, Joseph N, Haggarty SJ, Delalle I, Tsai LH. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 2012 Mar 8;483(7388):222-6. PubMed.

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References

News Citations

1. Of Mice and Men—Functional Imaging of Aβ Toxicity, Early Pathology 9 Oct 2007
2. For Better Memory, Try Keeping Your HAT On… 25 Jun 2004
3. Histone Acetylation: Epigenetic Achilles’ Heel of Memory in Aging 6 May 2010
4. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified 12 May 2009
5. Does Epigenetic Modification by Aβ Offer New Take on Therapy? 7 Mar 2012

Paper Citations

1. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006 Oct;112(4):389-404. PubMed.
2. Gómez-Isla T, Price JL, McKeel DW, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J Neurosci. 1996 Jul 15;16(14):4491-500. PubMed.
3. Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.
4. Small SA, Tsai WY, DeLaPaz R, Mayeux R, Stern Y. Imaging hippocampal function across the human life span: is memory decline normal or not?. Ann Neurol. 2002 Mar;51(3):290-5. PubMed.
5. Small SA, Chawla MK, Buonocore M, Rapp PR, Barnes CA. Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7181-6. PubMed.
6. Zhang Q, Vo N, Goodman RH. Histone binding protein RbAp48 interacts with a complex of CREB binding protein and phosphorylated CREB. Mol Cell Biol. 2000 Jul;20(14):4970-8. PubMed.
7. Fass DM, Reis SA, Ghosh B, Hennig KM, Joseph NF, Zhao WN, Nieland TJ, Guan JS, Kuhnle CE, Tang W, Barker DD, Mazitschek R, Schreiber SL, Tsai LH, Haggarty SJ. Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology. 2013 Jan;64:81-96. Epub 2012 Jul 4 PubMed.

Other Citations

1. ARF conference story

External Citations

1. company news release

Further Reading

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