DISRUPT SLEEP, ERODE MEMORY NEUROSCIENCE: Amyloid-β peptide upsets deep-sleep state, leading to memory impairment ATIENTS WITH ALZHEIMER’S disease accumulate amyloid-β in their brains, forming plaques of the peptide. Many scientists think these deposits, or the high levels of the peptide itself, eventually lead to cognitive deficits, including memory loss. Researchers now report that the accumulating peptide may erode memory, in part by disrupting the deepest stage of sleep. The results, according to Bryce A. Mander of the University of California, Berkeley, and his colleagues, suggest that disrupted sleep could become an effective early marker for the disease and that improving the quality of sleep could improve cognitive function in Alzheimer’s patients (Nat. Neurosci. 2015, DOI: 10.1038/nn.4035). Although amyloid accumulation has been linked to memory dysfunction in people with Alzheimer’s, the underlying mechanism is unknown. One fact that complicates the amyloid-memory connection is that the peptide builds up largely in the front of the brain, in particular in the medial prefrontal cortex, away from the hippocampus, the region that facilitates memory formation. The UC Berkeley-led team thought nonrapid eye movement (NREM) sleep might be the key between the peptide and memory because of NREM’s connection to the medial prefrontal cortex. This dreamless part of sleep is the deepest, Mander says. “It’s the time when you are most knocked out and your brain is the farthest away from consciousness.” During NREM sleep, the medial prefrontal cortex generates large, slow electrical signals as many of its neurons fire in unison. Previous studies have shown
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that people are better at forming stable, long-term memories when they have more of this so-called slowwave activity during sleep. So Mander, a postdoc in the lab of Matthew P. Walker, wondered if greater accumulation of amyloid led to reduced slow-wave activity, and, in turn, poorer memory. Mander and his colleagues tested the hypothesis by studying 26 older adults who showed no signs of dementia or Alzheimer’s. They measured the amount of amyloid in their brains using positron emission tomography and a radiolabeled molecule that binds the peptide. The team asked the volunteers to learn 120 pairs of words before going to sleep in the lab for eight hours. The researchers measured brain activity during the night with electroencephalography. When the researchers used a statistical model to analyze the levels of amyloid, the amount of slow-wave activity, and the subjects’ memory of the word pairs the following day, they found a strong connection confirming the hypothesis. “The study’s conclusion is interesting and important, because it ties together several independent lines of research showing that amyloid can affect memory and sleep,” says Brendan P. Lucey of the Multidisciplinary Sleep Medicine Center at Washington University in St. Louis. But Lucey points out that more data are needed to strengthen this model. A multiyear study following a set of subjects, Lucey says, should allow researchers to watch how changes in amyloid levels lead to changes in sleep and memory. Mander says he and his colleagues have planned such an experiment and recently received funding to conduct it.—MICHAEL TORRICE
BRYCE A. MANDER AND MATTHEW P. WALKER
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Brain scans (top) highlight regions of low (left) and high (right) levels of amyloid-β. People with low levels produce large, lowfrequency brain waves during deep sleep (bottom left), whereas those with high levels produce fewer waves (bottom right).
OBITUARY Chemistry Nobel Laureate Irwin Rose dies at 88, shared prize for protein degradation studies Biochemist Irwin (Ernie) Rose, who shared the 2004 Nobel Prize in Chemistry for research on regulated protein degradation, died on June 2 at age 88. Rose spent much of his career as a research scientist at the Fox Chase Cancer Center in Philadelphia. There, he collaborated with fellow Nobel Prize winners Aaron Ciechanover and Avram Hershko of Technion—Israel Institute of Technology. Starting in the 1970s, the trio identified the small regulatory polypeptide, now known as ubiquitin, that cells attach to
other proteins to label them for degradation by a protease. The researchers went on to discover more proteins that activate ubiquitin and add it to targets. At the time of this research, attaching ubiquitin to a protein represented a new kind of posttranslational modification. “With his deep knowledge and ability to think far out of the box, Ernie was able to take us out of the swamp where we were drowning” to discover the mechanism of ubiquitin tagging, Ciechanover says. Rose “also contributed enormously to
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our understanding of enzyme function in general, creating novel methodologies and new ways of thinking about reaction mechanisms,” says Judith P. Klinman, a chemistry professor at the University of California, Berkeley. Klinman worked with Rose as a postdoctoral researcher and later as a colleague at Fox Chase. Adds Klinman, “He was a formidable example of how to pursue basic research with curiosity, integrity, and a fierce determination to uncover the ‘truth’ behind the question at hand.”—JYLLIAN KEMSLEY
