How Does TREM2 Help the Brain Clean out Molecular “Garbage” that Contributes to Alzheimer’s

Charles Sanders, PhD
Vanderbilt University Medical Center (Nashville, TN)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015565S
Award Type:
Standard
Award Region:
US Midwestern
Charles Sanders, PhD

TREM2 and Alzheimer's Disease

Summary

An immune molecule known as triggering receptor expressed on myeloid cells 2, or TREM2, is a protein that plays a major role in helping the brain to cleanse itself of toxic substances that contribute to Alzheimer’s disease (AD) and related disorders. Defects in this protein make it unable to carry out its job in the brain, leading to the accumulation of toxic hazards. The goal of our work is to take a molecular snapshot of the TREM2 molecule (a picture is worth a thousand words) and to examine how it interacts with toxic molecules in the brain. We expect this work to provide information needed to design potential AD treatments that are based on helping TREM2 do its job.

Details

We seek to unravel the role that the TREM2 protein plays in helping to prevent AD and to provide a better understanding of what exactly goes wrong, contributing to AD, when this protein no longer can do its job.

The TREM2 protein plays a role in the immune system of the brain and seems to assist in clearing the brain of toxic entities, including excessive and misshapen forms of two amyloid proteins that may promote AD, amyloid beta (Aβ) and tau. Inherited defects in TREM2 appear to increase patient risk not only for AD, but also for Parkinson’s disease and amyloid lateral sclerosis (ALS, also known as Lou Gehrig’s disease). Thus, TREM2 appears be on a central pathway in the brain that, when all goes well, helps to prevent or delay the onset of multiple neurodegenerative diseases.

The aims of this project are:

Aim 1. Purify TREM2 and take a high resolution snapshot of this protein. To understand how TREM2 works normally under healthy conditions, or fails to work under disease conditions, we need to know what the molecule looks like. Because protein molecules are so very small, taking such a picture requires us to use state-of-the-art molecular imaging methods.  We will take pictures of both the healthy form of TREM2 and of a defective form known to be associated with AD.

Aim 2.  Determine what molecules TREM2 binds to. TREM2 may perform its AD-preventative function, in part, by recognizing and directly latching onto toxic molecules in the brain. We will use purified TREM2 and test whether it, in fact, can latch onto (think Velcro-type adhesion) prime suspect molecules, such as various forms of the Aβ polypeptide that many believe underlies the development of AD.

Aim 3.  Examine the interactions of TREM2 with the death-associated protein 12 (DAP12). TREM2 has a protein partner that helps it carry out its role in maintaining a healthy brain: the DAP12 protein.  It is thought that when TREM2 latches onto a potentially toxic molecule in the brain, DAP12 senses this and is thereby prompted to signal to host brain cells that it needs to respond in a ways that promote a healthy brain, which may include programmed cell death.  Just as for TREM2, we wish to take a high resolution snapshot of DAP12 and examine in detail how it senses binding of toxic molecules by TREM2.

Completing these aims will advance our understanding of what exactly TREM2 does to help prevent Alzheimer’s and how TREM2 and its DAP12 partner work to accomplish this.  Such information will provide the basis for developing strategies for preventing or even treating AD and other neurodegenerative diseases based on supporting or even enhancing the TREM2/DAP12 system.

About the Researcher

Chuck Sanders graduated from Milligan College with a degree in chemistry and mathematics in 1983. He completed his PhD in chemistry at The Ohio State University in 1988, and then studied biophysics as a National Institutes of Health (NIH) Postdoctoral Fellow at Yale University from 1989-1991. He next joined the physiology and biophysics faculty at Case Western Reserve University School of Medicine.  In 2002, he moved to Nashville, Tenn., where he is a Professor of Biochemistry and holds an endowed chair at the Vanderbilt University School of Medicine. Dr. Sanders has served on numerous grant review panels, including two full terms of duty as a member of NIH study sections. He also is the recipient of the Anatrace Membrane Protein Award of the Biophysical Society (2012), and the Hans Neurath Award of the Protein Society (2013). The Sanders lab is focused on research in the area of membrane protein biochemistry and structural biology.  In particular Dr. Sanders is interested in discovering how membrane proteins contribute to human diseases.  



"Growing up in the 1960s, Chuck Sanders was initially led to science by the optimistic notion that it could help him to become a dinosaur.  While that did not work out, the science hook became even more firmly set by the glory of the Apollo space program and backyard astronomy. Accompanied in life by his wife Becky, and three sons, Dr. Sanders started the faculty phase of his career in 1991.

Following a decade of pursuing “basic science” questions, during the 1990s, the Sanders lab had reached a stage of expertise and interests where it clearly was time to pursue research that is directly disease-relevant. That led to the first Sanders lab project on Alzheimer’s disease (AD).   Dr. Sanders’ interest became very personal when his father was diagnosed with AD a few years ago.  As of 2015, he is still able to live at home with Dr. Sanders’ mother, but he has forgotten who she is."

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