Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

Abstract

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 by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation. To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. 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 the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.

Structural Basis of Plant Homeodomain Finger 6 (PHF6) Recognition by the Retinoblastoma Binding Protein 4 (RBBP4) Component of the Nucleosome Remodeling and Deacetylase (NuRD) Complex

“…The NuRD complex is the only RBBP4-containing complex known to interact with the PHF6 protein, but it is possible that PHF6 might associate with other RBBP4-containing complexes, such as the CAF-1 and PRC2 complexes, in a parallel manner. RBBP4/RbAp48 decline in the dentate gyrus is responsible for age-related memory loss (37), and the PHF6 gene is associated with human Börjeson-Forssman-Lehmann syndrome, an X-linked mental retardation disorder, and is also expressed in the dentate gyrus in the adult brain (17). However, it is unclear whether there is a relationship between RBBP4-PHF6 interaction and human mentality and memory.…”

Mechanisms of electromagnetic influences and effects on membrane systems in neurons and cardiomyocytes

“…Bioelectrical activity of the neurons in mollusks and warmblooded animals is mainly provided by the ac tivity of sodium, calcium and potassium ion channels, which are built and operate according to the same general principles [3][4][5][6][7][8]. It enable us to use the neu rons of mollusks as eligible models [9][10][11][12][13][14][15][16][17][18], in paral lel with the neurons of warmblooded animals, for experimental research on the performance of the ion channels and the mechanisms of influences on them made by various physical factors, chemical substanc es and pharmaceutical drugs either of already known nature or being designed.…”

Rbap48 Could Act as a Candidate Biological Predictor for the Cognition Impairments of Patients with Temporal Lobe Epilepsy: A Hypothesis Based on Recent Molecular Findings

“…Extensive investigations have focused on the hippocampus to form a conceptual framework of the architecture of diverse memory systems. It is well understood that RbAp48 participates in the age-related DG dysfunction and the expression level decreases in ageing hippocampus of human and mice [12,18]. The deficiency of RbAp48 in the DG has been suspected as the underlying cause of age-related memory deficits.…”

“…Patients with a longer duration of refractory TLE would exhibit more severe cognitive impairments. Understanding of the neurobiology of disordered cognition especially the memory loss in epilepsy was accelerated by the development of organized epilepsy surgery Furthermore, it had been found that up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated their age-related memory loss, and restored their memory to youthful vigor [12]. So it is a logical next step to test these RbAp48 expression enhancers for therapeutic use against the memory deterioration in TLE animal models, and ultimately in TLE patients.…”

“…Thus RbAp48 is considered as a positive regulator of human neurogenesis owing to its ability to regulate the expression of the pluripotency, differentiation, and cell cycle genes in human PSCs. Moreover, the deficiency of RbAp48 plays a pivotal role in the DG dysfunction and it is closely related to agerelated memory deficits [12]. The human hippocampus can be affected by a large variety of very different neurological diseases, of which the epilepsy, acute ischemic stroke, transient global amnesia, and limbic encephalitis are the most common causes [13].…”