Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study details molecular roots of Alzheimer's

21.12.2016

Cellular 'housekeeping' molecule's structure linked to neurodegeneration

Scientists at Washington University School of Medicine in St. Louis have detailed the structure of a molecule that has been implicated in Alzheimer's disease. Knowing the shape of the molecule -- and how that shape may be disrupted by certain genetic mutations -- can help in understanding how Alzheimer's and other neurodegenerative diseases develop and how to prevent and treat them.


A new study at Washington University School of Medicine in St. Louis details the structure of TREM2, a protein involved in Alzheimer's disease and other neurodegenerative disorders. Researchers found that mutations associated with Alzheimer's alter the surface of the protein, while mutations linked to another brain disorder disrupt the protein's interior. Such alterations may impair TREM2's normal role in cleaning up cellular waste via a process called phagocytosis.

Credit: Daniel L. Kober

The study is published Dec. 20 in the journal eLife.

The idea that the molecule TREM2 is involved in cognitive decline -- the hallmark of neurodegenerative diseases, including Alzheimer's -- has gained considerable support in recent years. Past studies have demonstrated that certain mutations that alter the structure of TREM2 are associated with an increased risk of developing late-onset Alzheimer's, frontal temporal dementia, Parkinson's disease and sporadic amyotrophic lateral sclerosis (ALS). Other TREM2 mutations are linked to Nasu-Hakola disease, a rare inherited condition that causes progressive dementia and death in most patients by age 50.

"We don't know exactly what dysfunctional TREM2 does to contribute to neurodegeneration, but we know inflammation is the common thread in all these conditions," said senior author Thomas J. Brett, PhD, an assistant professor of medicine. "Our study looked at these mutations in TREM2 and asked what they do to the structure of the protein itself, and how that might impact its function. If we can understand that, we can begin to look for ways to correct it."

The analysis of TREM2 structure, completed by first author, Daniel L. Kober, a doctoral student in Brett's lab, revealed that the mutations associated with Alzheimer's alter the surface of the protein, while those linked to Nasu-Hakola influence the "guts" of the protein. The difference in location could explain the severity of Nasu-Hakula, in which signs of dementia begin in young adulthood. The internal mutations totally disrupt the structure of TREM2, resulting in fewer TREM2 molecules. The surface mutations, in contrast, leave TREM2 intact but likely make it harder for the molecule to connect to proteins or send signals as normal TREM2 molecules would.

TREM2 lies on the surface of immune cells called microglia, which are thought to be important "housekeeping" cells. Via a process called phagocytosis, such cells are responsible for engulfing and cleaning up cellular waste, including the amyloid beta that is known to accumulate in Alzheimer's disease. If the microglia lack TREM2, or the TREM2 that is present doesn't function properly, the cellular housekeepers can't perform their cleanup tasks.

"Exactly what TREM2 does is still an open question," Brett said. "We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology. Now that we have these structures, we can study how TREM2 works, or doesn't work, in these neurodegenerative diseases."

TREM2 also has been implicated in other inflammatory conditions, including chronic obstructive pulmonary disease and stroke, making the structure of TREM2 important for understanding chronic and degenerative diseases throughout the body, he added.

###

This work was supported by the National Institutes of Health (NIH), grant numbers R01-HL119813, R01-AG044546, R01-AG051485, R01-HL120153, R01-HL121791, K01-AG046374, T32-GM007067, K08-HL121168, and P50-AG005681-30.1; the Burroughs-Wellcome Fund; the Alzheimer's Association, grant number AARG-16-441560; and the American Heart Association, grant number PRE22110004. Results were derived from work performed at Argonne National Laboratory (ANL) Structural Biology Center. ANL is operated by U. Chicago Argonne, LLC, for the U.S. DOE, Office of Biological and Environmental Research, supported by grant number DE-AC02-06CH11357.

Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife. Dec. 20, 2016.

Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Media Contact

Diane Duke Williams
williamsdia@wustl.edu
314-286-0111

 @WUSTLmed

http://www.medicine.wustl.edu 

Diane Duke Williams | EurekAlert!

More articles from Health and Medicine:

nachricht The cytoskeleton of neurons has been found to be involved in Alzheimer's disease
18.01.2019 | University of the Basque Country

nachricht Bioinspired nanoscale drug delivery method developed by WSU, PNNL researchers
10.01.2019 | Washington State University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Ten-year anniversary of the Neumayer Station III

The scientific and political community alike stress the importance of German Antarctic research

Joint Press Release from the BMBF and AWI

The Antarctic is a frigid continent south of the Antarctic Circle, where researchers are the only inhabitants. Despite the hostile conditions, here the Alfred...

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Additive manufacturing reflects fundamental metallurgical principles to create materials

18.01.2019 | Materials Sciences

How molecules teeter in a laser field

18.01.2019 | Life Sciences

The cytoskeleton of neurons has been found to be involved in Alzheimer's disease

18.01.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>