Gene Key To Alzheimer's-like Reversal Identified: Success In Restoring Memories In Mice Could Lead To Human Treatments

A team led by researchers at MIT's Picower Institute for Learning and Memory has now pinpointed the exact gene responsible for a 2007 breakthrough in which mice with symptoms of Alzheimer's disease regained long-term memories and the ability to learn.In the latest development, reported in the May 7 issue of Nature, Li-Huei Tsai, Picower Professor of Neuroscience, and colleagues found that drugs that work on the gene HDAC2 reverse the effects of Alzheimer's and boost cognitive function in mice.

"This gene and its protein are promising targets for treating memory impairment," Tsai said. "HDAC2 regulates the expression of a plethora of genes implicated in plasticity — the brain's ability to change in response to experience — and memory formation.

"It brings about long-lasting changes in how other genes are expressed, which is probably necessary to increase numbers of synapses and restructure neural circuits, thereby enhancing memory," she said.

The researchers treated mice with Alzheimer's-like symptoms using histone deacetylase (HDAC) inhibitors. HDACs are a family of 11 enzymes that seem to act as master regulators of gene expression. Drugs that inhibit HDACs are in experimental stages and are not available by prescription for use for Alzheimer's.

"Harnessing the therapeutic potential of HDAC inhibitors requires knowledge of the specific HDAC family member or members linked to cognitive enhancement," Tsai said. "We have now identified HDAC2 as the most likely target of the HDAC inhibitors that facilitate synaptic plasticity and memory formation.

"This will help elucidate the mechanisms by which chromatin remodeling regulates memory," she said. It also will shed light on the role of epigenetic regulation, through which gene expression is indirectly influenced, in physiological and pathological conditions in the central nervous system.

"Furthermore, this finding will lead to the development of more selective HDAC inhibitors for memory enhancement," she said. "This is exciting because more potent and safe drugs can be developed to treat Alzheimer's and other cognition diseases by targeting this HDAC specifically," said Tsai, who is also a Howard Hughes Medical Institute investigator. Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. Researchers have had promising results with HDAC inhibitors in mouse models of Huntington's disease.

Remodeling structures

Proteins called histones act as spools around which DNA winds, forming a structure in the cell nucleus known as chromatin. Histones are modified in various ways, including through a process called acetylation, which in turn modifies chromatin shape and structure. (Inhibiting deacetylation with HDAC inhibitors leads to increased acetylation.)

Certain HDAC inhibitors open up chromatin. This allows transcription and expression of genes in what had been a too tightly packaged chromatin structure in which certain genes do not get transcribed.

There has been exponential growth in HDAC research over the past decade. HDAC inhibitors are currently being tested in preclinical studies to treat Huntington's disease. Some HDAC inhibitors are on the market to treat certain forms of cancer. They may help chemotherapy drugs better reach their targets by opening up chromatin and exposing DNA. "To our knowledge, HDAC inhibitors have not been used to treat Alzheimer's disease or dementia," Tsai said. "But now that we know that inhibiting HDAC2 has the potential to boost synaptic plasticity, synapse formation and memory formation, in the next step, we will develop new HDAC2-selective inhibitors and test their function for human diseases associated with memory impairment to treat neurodegenerative diseases."

The researchers conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. Following Alzheimer's-like brain atrophy, the mice acted as though they did not remember tasks they had previously learned.

But after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

The fact that long-term memories can be recovered by elevated histone acetylation supports the idea that apparent memory "loss" is really a reflection of inaccessible memories, Tsai said. "These findings are in line with a phenomenon known as 'fluctuating memories,' in which demented patients experience temporary periods of apparent clarity," she said.

In addition to Tsai, co-authors are Picower postdoctoral associate Ji-Song Guan; and colleagues from Massachusetts General Hospital; Harvard Medical School; the Whitehead Institute for Biomedical Research; MIT's Department of Biology; the Dana Farber Cancer Institute; and the Netherlands Cancer Institute.

This work is supported by the National Institute for Neurological Disorders and Stroke, the Stanley Center for Psychiatric research at the Broad Institute of Harvard and MIT; the NARSAD, a mental health foundation, the National Cancer Institute, the Damon-Runyon Cancer Research Foundation; the Dutch Cancer Society; the National Institutes of Health; and the Robert A. and Renee E. Belfer Institute for Applied Cancer Science.

Ginger Quells Cancer Patients' Nausea From Chemotherapy

People with cancer can reduce post-chemotherapy nausea by 40 percent by using ginger supplements, along with standard anti-vomiting drugs, before undergoing treatment, according to scientists at the University of Rochester Medical Center.About 70 percent of cancer patients who receive chemotherapy complain of nausea and vomiting. "There are effective drugs to control vomiting, but the nausea is often worse because it lingers," said lead author Julie L. Ryan, Ph.D., M.P.H., assistant professor of Dermatology and Radiation Oncology at Rochester's James P. Wilmot Cancer Center. The research will be presented at the American Society of Clinical Oncology meeting in the Patient and Survivor Care Session on Saturday, May 30, in Orlando, Fla.

"Nausea is a major problem for people who undergo chemotherapy and it's been a challenge for scientists and doctors to understand how to control it," said Ryan, a member of Rochester's Community Clinical Oncology Program Research Base at the Wilmot Cancer Center. Her research is the largest randomized study to demonstrate the effectiveness of ginger supplements to ease the nausea. Previous small studies have been inconsistent and never focused on taking the common spice before chemotherapy.

The Phase II/III placebo-controlled, double-blind study included 644 cancer patients who would receive at least three chemotherapy treatments. They were divided into four arms that received placebos, 0.5 gram of ginger, 1 gram of ginger, or 1.5 grams of ginger along with antiemetics (anti-vomiting drugs such as Zofran®, Kytril®, Novaban®, and Anzemet®.)

Patients took the ginger supplements three days prior to chemotherapy and three days following treatment. Patients reported nausea levels at various times of day during following their chemotherapy and those who took the lower doses had a 40 percent reduction.

Ginger is readily absorbed in the body and has long been considered a remedy for stomach aches. "By taking the ginger prior to chemotherapy treatment, the National Cancer Institute-funded study suggests its earlier absorption into the body may have anti-inflammatory properties," Ryan said.

Rochester's Community Clinical Oncology Program Research Base is a national cooperative research group funded by the National Cancer Institute. The Wilmot Cancer Center team specializes in improving the quality of life of people who have cancer.