neurobiology
New Study Points to Targetable Protective Factor in Alzheimer’s Disease
Posted on by Dr. Francis Collins
If you’ve spent time with individuals affected with Alzheimer’s disease (AD), you might have noticed that some people lose their memory and other cognitive skills more slowly than others. Why is that? New findings indicate that at least part of the answer may lie in differences in their immune responses.
Researchers have now found that slower loss of cognitive skills in people with AD correlates with higher levels of a protein that helps immune cells clear plaque-like cellular debris from the brain [1]. The efficiency of this clean-up process in the brain can be measured via fragments of the protein that shed into the cerebrospinal fluid (CSF). This suggests that the protein, called TREM2, and the immune system as a whole, may be promising targets to help fight Alzheimer’s disease.
The findings come from an international research team led by Michael Ewers, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München, Germany, and Christian Haass, Ludwig-Maximilians-Universität München, Germany and German Center for Neurodegenerative Diseases. The researchers got interested in TREM2 following the discovery several years ago that people carrying rare genetic variants for the protein were two to three times more likely to develop AD late in life.
Not much was previously known about TREM2, so this finding from a genome wide association study (GWAS) was a surprise. In the brain, it turns out that TREM2 proteins are primarily made by microglia. These scavenging immune cells help to keep the brain healthy, acting as a clean-up crew that clears cellular debris, including the plaque-like amyloid-beta that is a hallmark of AD.
In subsequent studies, Haass and colleagues showed in mouse models of AD that TREM2 helps to shift microglia into high gear for clearing amyloid plaques [2]. This animal work and that of others helped to strengthen the case that TREM2 may play an important role in AD. But what did these data mean for people with this devastating condition?
There had been some hints of a connection between TREM2 and the progression of AD in humans. In the study published in Science Translational Medicine, the researchers took a deeper look by taking advantage of the NIH-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).
ADNI began more than a decade ago to develop methods for early AD detection, intervention, and treatment. The initiative makes all its data freely available to AD researchers all around the world. That allowed Ewers, Haass, and colleagues to focus their attention on 385 older ADNI participants, both with and without AD, who had been followed for an average of four years.
Their primary hypothesis was that individuals with AD and evidence of higher TREM2 levels at the outset of the study would show over the years less change in their cognitive abilities and in the volume of their hippocampus, a portion of the brain important for learning and memory. And, indeed, that’s exactly what they found.
In individuals with comparable AD, whether mild cognitive impairment or dementia, those having higher levels of a TREM2 fragment in their CSF showed a slower decline in memory. Those with evidence of a higher ratio of TREM2 relative to the tau protein in their CSF also progressed more slowly from normal cognition to early signs of AD or from mild cognitive impairment to full-blown dementia.
While it’s important to note that correlation isn’t causation, the findings suggest that treatments designed to boost TREM2 and the activation of microglia in the brain might hold promise for slowing the progression of AD in people. The challenge will be to determine when and how to target TREM2, and a great deal of research is now underway to make these discoveries.
Since its launch more than a decade ago, ADNI has made many important contributions to AD research. This new study is yet another fine example that should come as encouraging news to people with AD and their families.
References:
[1] Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C; Alzheimer’s Disease Neuroimaging Initiative. Sci Transl Med. 2019 Aug 28;11(507).
[2] Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Nat Neurosci. 2019 Feb;22(2):191-204.
Links:
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
Alzheimer’s Disease Neuroimaging Initiative (University of Southern California, Los Angeles)
Ewers Lab (University Hospital Munich, Germany)
Haass Lab (Ludwig-Maximilians-Universität München, Germany)
German Center for Neurodegenerative Diseases (Bonn)
Institute for Stroke and Dementia Research (Munich, Germany)
NIH Support: National Institute on Aging
From Songbird Science to Salsa Dancing
Posted on by Dr. Francis Collins
Erich Jarvis spends his days at the Rockefeller University, New York, studying songbirds and searching for clues about the origins of language. But at least two nights a week, you won’t find this highly accomplished neurobiologist mulling over the latest neuroscience results or shooting an email to colleagues about their ongoing efforts to sequence bird genomes. He’ll be in the dance studio, practicing his latest salsa dancing moves.
In fact, before even considering a career as a scientist, Jarvis was a dancer. He danced ballet in grade school, later enrolling in New York’s High School of the Performing Arts as a dance major. Between academic classes, he spent three hours each day practicing ballet at school and, as a teen, another three hours each night practicing solos and pas de deux at the renowned Joffrey Ballet School and, later, the Alvin Ailey American Dance School. Jarvis even received an invitation as a high school senior to audition for the Alvin Ailey American Dance Theater.
NIH Family Members Giving Back: Kafui Dzirasa
Posted on by Dr. Francis Collins
Caption: Kafui Dzirasa (front center) with the current group of Meyerhoff Scholars at University of Maryland, Baltimore County.
Credit: Olubukola Abiona
Kafui Dzirasa keeps an open-door policy in his busy NIH-supported lab at Duke University, Durham, NC. If his trainees have a quick question or just need to discuss an upcoming experiment, they’re always welcome to pull up a chair. The donuts are on him.
But when trainees pop by his office and see he’s out for the day, they have a good idea of what it means. Dzirasa has most likely traveled up to his native Maryland to volunteer as a mentor for students in a college program that will be forever near and dear to him. It’s the Meyerhoff Scholars Program at the University of Maryland, Baltimore County (UMBC). Since its launch in 1988, this groundbreaking program has served as a needed pipeline to help increase diversity in the sciences—with more than 1,000 alumni, including Dzirasa, and 270 current students of all races.
Creative Minds: A Transcriptional “Periodic Table” of Human Neurons
Posted on by Dr. Francis Collins
Caption: Mouse fibroblasts converted into induced neuronal cells, showing neuronal appendages (red), nuclei (blue) and the neural protein tau (yellow).
Credit: Kristin Baldwin, Scripps Research Institute, La Jolla, CA
Writers have The Elements of Style, chemists have the periodic table, and biomedical researchers could soon have a comprehensive reference on how to make neurons in a dish. Kristin Baldwin of the Scripps Research Institute, La Jolla, CA, has received a 2016 NIH Director’s Pioneer Award to begin drafting an online resource that will provide other researchers the information they need to reprogram mature human skin cells reproducibly into a variety of neurons that closely resemble those found in the brain and nervous system.
These lab-grown neurons could be used to improve our understanding of basic human biology and to develop better models for studying Alzheimer’s disease, autism, and a wide range of other neurological conditions. Such questions have been extremely difficult to explore in mice and other animal models because they have shorter lifespans and different brain structures than humans.
All Scientific Hands on Deck to End the Opioid Crisis
Posted on by Dr. Nora Volkow and Dr. Francis Collins
In 2015, 2 million people had a prescription opioid-use disorder and 591,000 suffered from a heroin-use disorder; prescription drug misuse alone cost the nation $78.5 billion in healthcare, law enforcement, and lost productivity. But while the scope of the crisis is staggering, it is not hopeless.
We understand opioid addiction better than many other drug use disorders; there are effective strategies that can be implemented right now to save lives and to prevent and treat opioid addiction. At the National Rx Drug Abuse and Heroin Summit in Atlanta last April, lawmakers and representatives from health care, law enforcement, and many private stakeholders from across the nation affirmed a strong commitment to end the crisis.
Research will be a critical component of achieving this goal. Today in the New England Journal of Medicine, we laid out a plan to accelerate research in three crucial areas: overdose reversal, addiction treatment, and pain management [1].
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