Detailing the Molecular Roots of Alzheimer’s Disease

TREM2
TREM2 is a protein involved in Alzheimer’s disease and other neurodegenerative disorders. Its electrostatic surface structure, depicted here, was determined at the Structural Biology Center X-ray facility at the Advanced Photon Source at Argonne National Laboratory. [From Kober, D. L., et al. “Neurodegenerative Disease Mutations in TREM2 Reveal a Functional Surface and Distinct Loss-of-Function Mechanisms.” eLife 5, e20391 (2016). DOI:10.7554/eLife.20391. Reused under a Creative Commons license (CC BY 4.0, https://creativecommons.org/licenses/by/4.0/).]
Scientists have captured the three-dimensional (3D) detail of the structure of a molecule implicated in Alzheimer’s disease. Knowing the shape of this 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.

From past studies, scientists think that the molecule TREM2 possibly is involved in cognitive decline, the hallmark of neurodegenerative diseases, because 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.Although its exact contribution is unknown, dysfunctional TREM2 does relate to neurodegeneration, and “inflammation is the common thread in all these conditions.” The scientists investigated what TREM2 mutations do to the structure of the protein itself to impact its function, so ways can be found to correct it.

Structural analysis of TREM2 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 involved in, for example, maintaining healthy brain biology via a process called phagocytosis that cleans cellular waste, including the amyloid beta that is known to accumulate in Alzheimer’s disease. If the microglia lack TREM2 or the TREM2 is dysfunctional, these cellular housekeepers can’t perform their cleanup tasks. Though the exact function of TREM2 is still unknown, mice without TREM2 have defects in their microglia. With these structural data, scientists can study how TREM2 works, or doesn’t work, in these neurodegenerative diseases, as well as other inflammatory conditions including chronic obstructive pulmonary disease and stroke. The structure of TREM2 could be important for understanding many chronic and degenerative diseases.

Kober, D. L., et al. “Neurodegenerative Disease Mutations in TREM2 Reveal a Functional Surface and Distinct Loss-of-Function Mechanisms,” eLife 5, e20391 (2016). [DOI:10.7554/eLife.20391].

Instruments and Facilities Used: X-ray Facility at the Advanced Photon Source (APS) at Argonne National Laboratory

Funding Acknowledgements (from publication): NIH, Knight Alzheimer’s Disease Research Center, Alzheimer’s Association Research Grant, Burroughs-Wellcome Fund Career Award for Medical Scientists, and American Heart Association Predoctoral Fellowship.