A high level of an enzyme that causes the deacetylation of histones associated with genes important for learning and memory may be a common feature that mediates the cognitive impairment seen in animal models of Alzheimer’s disease and human patients with the disease.
Inhibition of this gene, which codes for histone deacetylase 2 (HDAC2), may be a good approach to test therapeutically in further studies of animal models of Alzheimer’s disease, noted Johannes Gräff, Ph.D., and his colleagues, who were led by Li-Huei Tsai, Ph.D., of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, Cambridge.
Courtesy of Dr. Li-Huei Tsai
Dr. Li-Huei Tsai
Over the past decade, other studies have noted sporadic cases of reduced histone acetylation in animal models of neurodegeneration that are characterized by cognitive decline, including Alzheimer’s disease. These studies have shown success in reducing cognitive decline in mouse models of Alzheimer’s through the use of nonselective HDAC inhibitors. The results of the current study by Dr. Tsai and her associates suggest that HDAC2 likely was the target of the nonselective inhibitors in earlier studies (Nature 2012;483:222-6).
"I really think this points to a new direction in thinking about therapeutic intervention or prevention" with a strategy that does not directly target amyloid-beta levels, Dr. Tsai said in an interview. While amyloid-beta plays a very early and important role in the disease, she suggested that once the pathogenic cascade of events is triggered, "there are a lot of biological processes that may become amyloid-independent."
Prior studies have shown how amyloid-beta can acutely impair synaptic plasticity by decreasing N-methyl-d-aspartate receptor functions, she said, but it may have a more profound and chronic effect on memory by inducing a blockade of the expression of many genes involved in different steps of memory formation and consolidation, she said.
In two different mouse models of Alzheimer’s disease, the investigators found elevated HDAC2 protein levels in neurodegenerating areas of the mice’s brains, including part of the hippocampus and in the prefrontal cortex. HDAC2 protein in the hippocampus of these mice was found bound to genes implicated in learning, memory, and synaptic plasticity. The investigators found that certain amino acids in the histones that bind to these genes had reduced acetylation, which is known to be important for learning, memory, and synaptic plasticity. All of these genes had reduced expression.
"Taken together, these results indicate that HDAC2 mediates a local chromatin compaction of neuroplasticity genes, which decreases their expression and may contribute to cognitive decline during neurodegeneration," Dr. Tsai and her associates wrote.
When the researchers blocked the expression of HDAC2, the acetylation of neuroplasticity genes increased. The regained expression of these genes induced morphological changes that increased synaptic density and the number of dendrites on surviving neurons, but did not alter neuronal survival.
Blocking HDAC2 in a mouse model of Alzheimer’s led to an improvement in associative and spatial memory – two types of hippocampus-dependent memory – indicating "that elevated HDAC2 levels are causally involved in the cognitive decline associated with neurodegeneration [in the mouse model], but that the prevention of HDAC2 upregulation rescues memory capabilities," the authors wrote.
The transcription of HDAC2 increased in primary hippocampal neurons after they were exposed in vitro to hydrogen peroxide and amyloid-beta oligomers – neurotoxic stimuli that are characteristic of Alzheimer’s disease–related neurodegeneration – as well as in the hippocampus of the mouse model. The effect of these stimuli on HDAC2 suggested to the researchers that transcriptional mechanisms might be involved. They found a binding site for the transcriptional regulator glucocorticoid receptor 1 within the HDAC2 gene. Activation of the glucocorticoid receptor is accomplished through phosphorylation, which the investigators detected in the hippocampi of the mouse model and in cultured hippocampal neurons after exposure to hydrogen peroxide and amyloid-beta oligomers. The hippocampi of these mice, as well as cultured hippocampal neurons stimulated with amyloid-beta oligomers, contained the phosphorylated glucocorticoid receptor 1 attached to the binding site on HDAC2. The binding site of glucocorticoid receptor 1 on HDAC2 was necessary for the transcriptional activation of HDAC2.
Post mortem brain specimens from patients at different stages of Alzheimer’s disease contained significantly elevated HDAC2 levels in the entorhinal cortex and a part of the hippocampus. The elevation of HDAC2 also was an early event in the progression of Alzheimer’s, judging from patients who died in Braak stage I and II.
Robert D. Moir, Ph.D., who studies biochemical and cellular mechanisms involved in neurodegeneration in Alzheimer’s disease and aging at MassGeneral Institute for Neurodegenerative Disease, Boston, said in an interview that the study is "terrific for supporting a role for HDAC2 in memory," but may be a "bit of an overreach in claiming that it is proof of blocking cognitive decline in the neurodegenerating brain. It may be true, but I think there needs to be a lot more work before that assertion can be really made."