From the WashU Newsroom…
Scientists drilling down to the molecular roots of Alzheimer’s disease have encountered a good news/bad news scenario. A major player is a gene called TREM2, mutations of which can substantially raise a person’s risk of the disease. The bad news is that in the early stages of the disease, high-risk TREM2 variants can hobble the immune system’s ability to protect the brain from amyloid beta, a key protein associated with Alzheimer’s.
The good news, however, according to researchers at Washington University School of Medicine in St. Louis, is that later in the disease, when the brain is dotted with toxic tangles of another Alzheimer’s protein known as tau, the absence of TREM2 protein seems to protect the brain from damage. Mice without TREM2 suffer much less brain damage than those with it.
The findings potentially make targeting the TREM2 protein as a means of preventing or treating the devastating neurodegenerative disease a little more complicated, and suggest that doctors may want to activate TREM2 early in the disease and tamp it down later.
“People in the Alzheimer’s field have already been trying to develop ways to target TREM2,” said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “Now that we have this data, the question is, ‘What does one really want to do? Stimulate it or inhibit it?’”
The study is published online the week of Oct. 9 in Proceedings of the National Academy of Sciences.
Amyloid beta plaques start forming in the brains of Alzheimer’s patients years before the characteristic symptoms of memory loss and confusion appear. The plaques themselves appear to do minimal damage – many older people remain mentally sharp despite plentiful plaques – but their presence raises the risk of developing tau tangles, the real engine of destruction. The brain starts to die specifically in the areas where tau tangles are found.
In the brain, the protein TREM2 is found only on immune cells known as microglia. Holtzman, along with Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology and Immunology, and others have shown that when TREM2 is absent, the immune cells can’t generate the energy they need to limit the spread of amyloid beta plaques.
Knowing that tau also plays a key role in the development of Alzheimer’s, Holtzman, graduate student Cheryl Leyns and Jason Ulrich, PhD, an assistant professor of neurology, decided to investigate the effect of TREM2 on tau.