January 23, 2019
The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences — called epigenetics — it was possible to reverse memory decline in an animal model of AD.
“In this paper, we have not only identified the epigenetic factors that contribute to memory loss, we also found ways to temporarily reverse them in an animal model of AD,” said senior author Zhen Yan, PhD, a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB.
The research was conducted on mouse models carrying gene mutations for familial AD — where more than one member of a family has the disease — and on post-mortem brain tissues from AD patients.
AD is linked to an epigenetic abnormality
AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.
The epigenetic changes in AD happen primarily in the later stages when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan said. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
“We found that in Alzheimer’s disease, many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory,” Yan said.
The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.
Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery.
“This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits,” Yan said.
Potential drug targets
Understanding that process has revealed potential drug targets, she said since repressive histone modification is controlled or catalyzed by enzymes.
“Our study not only reveals the correlation between epigenetic changes and AD, but we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors,” Yan said.
The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.
“When we gave the AD animals this enzyme inhibitor, we saw the rescue of cognitive function confirmed through evaluations of recognition memory, spatial memory, and working memory. We were quite surprised to see such dramatic cognitive improvement,” Yan said.
“At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”
The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.
“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function,” she explained.
“We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer’s disease,” Yan concluded. “If many of the dysregulated genes in AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”
The study was funded by a $2 million National Institutes of Health grant focused on novel treatment strategies for AD.
Other UB co-authors are Yan Zheng; Aiyi Liu; Zi-Jun Wang, PhD; Qing Cao, Ph.D.; Lin Lin; Kaijie Ma; Freddy Zhang; Jing Wei, PhD; Emmanuel Matas, PhD and Jia Cheng, Ph.D. Additional co-authors are Guo-Jun Chen of Chongqing Medical University, PhD, and Xiaomin Wang, MD, PhD., of the Beijing Institute for Brain Disorders, Capital Medical University.
University at Buffalo. “It may be possible to restore memory function in Alzheimer’s, preclinical study finds.” ScienceDaily. ScienceDaily, 23 January 2019. <www.sciencedaily.com/releases/2019/01/190123082255.htm>
Early prediction of Alzheimer’s progression: Blood protein
Years before symptoms of Alzheimer’s disease manifest, the brain starts changing and neurons are slowly degraded. Scientists at the German Center for Neurodegenerative Diseases (DZNE), the Hertie Institute for Clinical Brain Research (HIH) and the University Hospital Tuebingen now show that a protein found in the blood can be used to precisely monitor disease progression long before first clinical signs appear. This blood marker offers new possibilities for testing therapies. The study was carried out in cooperation with an international research team and published in the journal Nature Medicine.
“The fact that there is still no effective treatment for Alzheimer’s is partly because current therapies start much too late,” says Mathias Jucker, a senior researcher at the DZNE’s Tuebingen site and at the HIH. He headed the current study. In order to develop better treatments, scientists, therefore, need reliable methods to monitor and predict the course of the disease before symptoms such as memory changes occur. A blood test is better suited for this than e. g. expensive brain scans.
Recently, there was some progress in the development of such blood tests. Most of them are based on so-called amyloid proteins. In Alzheimer’s disease, amyloid proteins accumulate in the brain and also occur in the blood. However, Jucker and his colleagues take a different approach. “Our blood test does not look at the amyloid, but at what it does in the brain, namely neurodegeneration. In other words, we look at the death of neurons,” says Jucker.
Traces in the bloodstream
When brain cells die, their remains can be detected in the blood. “Normally, however, such proteins are rapidly degraded in the blood and are therefore not very suitable as markers for a neurodegenerative disease,” explains Jucker. “An exception, however, is a small piece of so-called neurofilament that is surprisingly resistant to this degradation.” The blood test of Jucker and colleagues is based on this protein. In the current study, the scientists show that neurofilament accumulates in the blood long before the onset of clinical symptoms (i.e. already during the so-called preclinical phase) and that it very sensitively reflects the course of the disease and enables predictions on future developments.
The study is based on data and samples from 405 individuals that were analyzed within an international research collaboration: the “Dominantly Inherited Alzheimer Network” (DIAN). In addition to the DZNE, the HIH and the University Hospital Tuebingen, the Washington University School of Medicine in St. Louis (USA) and other institutions all over the world are involved. This network investigates families in which Alzheimer’s disease already occurs in middle age due to certain gene variations. Genetic analyses allow very accurate predictions as to whether and when a family member will develop dementia.
Omens of dementia
Jucker and his colleagues monitored the development of neurofilament concentration in these individuals from year to year. Up to 16 years before the calculated onset of dementia symptoms, there were noticeable changes in the blood. “It is not the absolute neurofilament concentration, but its temporal evolution, which is meaningful and allows predictions about the future progression of the disease,” says Jucker. In fact, in further investigations, the scientists showed that changes in neurofilament concentration reflect neuronal degradation very accurately and allow predictions on how brain damage will develop. “We were able to predict loss of brain mass and cognitive changes that actually occurred two years later,” says Jucker.
While it turned out that the rate of change in neurofilament concentration was closely linked to brain degradation, correlation with the deposition of toxic amyloid proteins was far less pronounced. This supports the assumption that although amyloid proteins are triggers of disease, neuronal degradation occurs independently.
A tool for therapy research
Neurofilaments accumulate in the blood not only in Alzheimer’s but also in the course of other neurodegenerative disorders. Thus, the test is only conditionally suitable for diagnosing Alzheimer’s. “However, the test accurately shows the course of the disease and is, therefore, a powerful instrument for investigating novel Alzheimer’s therapies in clinical trials,” says Jucker
DZNE – German Center for Neurodegenerative Diseases. “Early prediction of Alzheimer’s progression: Blood protein.” ScienceDaily. ScienceDaily, 21 January 2019. <www.sciencedaily.com/releases/2019/01/190121115401.htm>.
Categories: Science & Technology