Stem cell molecule improves memory in mouse model of Alzheimer's disease
April 25, 2022
By Christopher Vaughan
Researchers at the Stanford School of Medicine have shown that one of the earliest pathological changes in a mouse model of Alzheimer’s disease is dysfunction in neural precursor cells (NPC), and that modifying NPC activity in these mice improved the memory problems that are a chief symptom of the Alzheimer’s.
Currently, most proposed therapies for Alzheimer’s disease target late-stage pathologies such as plaques and tangles, and none have proven very effective so far, said Michael Clarke, MD, the Karel H. and Avice N. Beekhuis Professor of Cancer Biology. “We wondered if targeting changes in neural precursor cells might be an earlier and more effective approach,” Clarke said. Clarke is senior author on a paper documenting their results, published in the journal eLife. Former graduate student Felicia Reinitz, MD, PhD, is first author on the paper.
Clarke’s research on the relationship between neural precursor cells and Alzheimer’s disease grew out of research done many years ago on a seemingly very different disorder: Down’s syndrome. Down’s syndrome is caused by an aberrant replication of chromosome 21 in the developing embryo. People with Down’s syndrome have 3 copies of chromosome 21 in their cells instead of two, and as a result, experience many developmental disorders such as brain defects and cardiovascular defects. In a dramatic finding, Clarke showed in 2013 that although there are thousands of genes on chromosome 21 that could possibly contribute to Down’s syndrome, in fact many of the signs of disease were due to the overactivity of just one gene, which produced the protein USP16. They also showed that too much USP16 suppressed stem cell activity. Reducing levels of USP16 promoted stem cell activation.
Clarke and his colleagues then began to focus one notable characteristic of people with Down syndrome. “If people with Down syndrome live into their 20s and 30s, they almost always start to develop Alzheimer’s disease,” Clarke said. “We wondered if USP16 might also be playing a role in the development of Alzheimer’s disease.”
The connection seemed plausible because mouse models of Alzheimer’s disease, in which mutated versions of amyloid precursor protein were introduced into the mouse genome, reduced the production of neural precursor cells, which are produced by brain stem cells and develop into various kinds of brain cells. In fact, reduced neural precursor cell production was the earliest sign of Alzheimer’s disease, long before the development of amyloid plaques and neurofibrillary tangles. Because Clarke had shown that changes in USP16 levels could either diminish stem cell replication or promote it, they thought that the molecule might help correct this early decline in neural precursor cell production.
“We wanted to see if decreasing USP16 would normalize the brain stem cell defects we saw in the mouse model of Alzheimer’s disease,” Reinitz said. “What we found was that it did.”
By manipulating the levels of USP16 in the Alzheimer mice, the researchers were able to restore normal levels of neural precursor cell production. But more importantly, they also showed that this also improved memory, which is the dominant feature of Alzheimer’s disease. “Since we care a lot about cognitive impairment, we were gratified to see that treated mice improved significantly on object recognition tests and learning mazes,” Reinitz says.
The researchers are aware that Alzheimer’s is a complex disease, and that amyloid plaques and neurofibrillary tangles certainly are involved in the disease, they said. But manipulating USP16 levels may ultimately prove to be a useful tool in treating Alzheimer’s, they added.
“USP16 seems to be one piece of the puzzle, a targetable component that has not been explored before,” Reinitz said. “This, in combination with other therapies, may allow us to treat the worst aspects Alzheimer’s disease.”