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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2019-11-26T00:00:00-05:00" class="date-display-single">November 26, 2019</span></p><div class='syndicate'><h1>Some Down syndrome problems reversed in mice</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>In a mouse model of Down syndrome, blocking a cellular pathway in brain cells improved learning and memory.</li>
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<li>Targeting this pathway with drugs may be a strategy for reducing the cognitive problems associated with Down syndrome.</li>
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</ul></div><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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<picture title="Down syndrome chromosome set">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=hXT0kvTn&timestamp=1574798945 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=6LJYc5Fs&timestamp=1574798945 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=iPi9RjUE&timestamp=1574798945 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=SQsn4HAv&timestamp=1574798945 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=m_jv8AAZ&timestamp=1574798945 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2019/20191126-trisomy.jpg?itok=6LJYc5Fs&timestamp=1574798945" alt="Down syndrome chromosome set" title="Down syndrome chromosome set" />
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</picture><span class="caption">Down syndrome is a genetic disease resulting from a chromosomal abnormality. People with Down syndrome inherit all or part of an extra copy of chromosome 21.</span><span class="credit">Darryl Leja, NHGRI</span></div>
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</div><p>Down syndrome is the most common genetic cause of intellectual disability. People born with the syndrome have deficits in learning and memory. They also have an increased risk of developing Alzheimer’s disease by middle age.</p>
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<p>Down syndrome is caused by an extra copy of chromosome 21. Scientists haven’t understood how the extra chromosome causes many of the brain and health problems associated with Down syndrome. One idea is that alterations of overall protein levels in the brain may affect learning and memory.</p>
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||
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<p>Researchers led by Drs. Mauro Costa-Mattioli from Baylor College of Medicine and Peter Walter from the University of California, San Francisco set out to examine how the disorder alters proteins in the brain. They used a mouse model of Down syndrome called Ts65Dn as well as brain tissue and cells from people with Down syndrome.</p>
|
||
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||
<p>The team focused on a cell signaling pathway called the integrated stress response (ISR). The ISR turns on to help protect the cell from dangerous conditions. One of its effects is to reduce protein production in the cell. The study was funded in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), National Human Genome Research Institute (NHGRI), and National Cancer Institute (NCI). Results were published on November 15, 2019, in <em>Science</em>.</p>
|
||
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||
<p>Compared with normal mice, protein production was reduced by about 40% in the hippocampus region in the brains of Ts65Dn mice. The hippocampus plays a central role in learning and memory formation. Further experiments showed that the ISR was persistently active in the hippocampus of the Ts65Dn mice.</p>
|
||
|
||
<p>To assess whether Down syndrome may also involve these changes, the team measured ISR activity in samples taken from brains and cells donated by people with Down syndrome. The samples had increased ISR activity as well.</p>
|
||
|
||
<p>ISR activity can be controlled by different enzymes. In the Ts65Dn mice, the team found, the increase in ISR activity in the hippocampus was driven by a specific enzyme called PKR. When they inhibited PKR—either genetically or with drugs—the mice had normal protein production levels. They were also able to perform similarly to normal mice on standard memory and behavior tests.</p>
|
||
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||
<p>Further experiments revealed that blocking PKR in the brains of Down syndrome mice improved communication between nerve cells—a process required for memory formation.</p>
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||
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<p>“The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation,” says Walter.</p>
|
||
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||
<p>“More than 10 years ago we discovered that the ISR serves as a molecular switch for the protein synthesis needed for long-term memory formation,” Costa-Mattioli explains. “In this study, we found that the switch is off in Down syndrome. More importantly, turning the switch back on in these mice reverses their long-term memory deficits.”</p>
|
||
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<p>Targeting the ISR with drugs may be a strategy for reducing the cognitive deficits associated with Down syndrome. More research is needed to understand whether such an approach might be feasible in people.</p>
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<p>—by Sharon Reynolds</p></div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nichd.nih.gov/health/topics/downsyndrome" target="_top">Down Syndrome</a></li><li><a href="https://www.nichd.nih.gov/health/topics/idds" target="_top">Intellectual and Developmental Disabilities (IDDs)</a></li><li><a href="https://ghr.nlm.nih.gov/condition/down-syndrome" target="_top">Down Syndrome—Genetics Home Reference</a></li><li><a href="https://www.nia.nih.gov/health/alzheimers-disease-people-down-syndrome" target="_top">Alzheimer's Disease in People with Down Syndrome</a></li><li><a href="https://www.nih.gov/include-project" target="_top">The INCLUDE Project</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://www.ncbi.nlm.nih.gov/pubmed/31727829">Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome.</a> Zhu PJ, Khatiwada S, Cui Y, Reineke LC, Dooling SW, Kim JJ, Li W, Walter P, Costa-Mattioli M. <em>Science</em>. 2019 Nov 15;366(6467):843-849. doi: 10.1126/science.aaw5185. PMID: 31727829.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Neurological Disorders and Stroke (NINDS), National Human Genome Research Institute (NHGRI), and National Cancer Institute (NCI); Sammons Enterprises; Howard Hughes Medical Institute.</p>
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-can-we-slow-aging">Research in Context: Can we slow aging?</a></p>
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|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/brain-changes-observed-during-pregnancy">Brain changes observed during pregnancy</a></p>
|
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|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/research-context-detecting-cancer">Research in Context: Detecting cancer</a></p>
|
||
|
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<p><a href="https://www.nih.gov/news-events/nih-research-matters/risk-future-burden-dementia-united-states">Risk and future burden of dementia in the United States </a></p>
|
||
|
||
<p><a href="https://www.nih.gov/news-events/nih-research-matters/complete-wiring-map-adult-fruit-fly-brain">Complete wiring map of an adult fruit fly brain</a></p>
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<h3 class="block__title">About NIH Research Matters</h3>
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<p><strong>Editor:</strong> Harrison Wein, Ph.D.</p>
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<p><strong>Assistant Editors:</strong> Vicki Contie and Brian Doctrow, Ph.D.</p>
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<p><strong><em>NIH Research Matters </em></strong>is a weekly update of NIH research highlights reviewed by NIH’s experts. It's published by the <a href="/institutes-nih/nih-office-director/office-communications-public-liaison">Office of Communications and Public Liaison</a> in the <a href="/institutes-nih/nih-office-director">NIH Office of the Director</a>.</p>
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<p>ISSN 2375-9593</p>
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