In 1993, neurologist Warren Strittmatter took the medical world by storm with the discovery of apolipoprotein E-4 (ApoE-4)1. It was the first gene found to be strongly associated with an increased risk of late onset Alzheimer’s disease (AD). Today, over 20 genetic loci have been implicated with AD. In this article, we explore the function and potential role that one of these genes, TREM2 (triggering receptor expressed on myeloid cells 2), may play.

TREM2 mutations may confer both protective and destructive effects in AD pathology, reveals study

TREM2 is intricately involved in the immune system. It is receptor that is found in high concentrations on microglia, a type of brain macrophage. Under normal circumstances, TREM2 plays an important role in maintaining immune system homeostasis in the central nervous system2. As we will soon discuss, the discovery of TREM2 mutations lend credence to the role of neuroinflammation in AD.

There are two hallmarks in AD pathology – amyloid-beta plaques and neurofibrillary tangles consisting of tau protein3. Mutations resulting in a loss of function of TREM2 gene have been shown to worsen the damage from amyloid-beta plaque toxicity. Amyloid-beta plaques are thought to incite an inflammatory response in the brain. TREM2 compensates by causing microglial activation which functions to clear plaque build-up2.

Given the known functions of TREM2, everyone was surprised when a recent study demonstrated that a loss of function in the gene yielded the opposite effects in the presence of only tau proteins. A team from the Washington University School of Medicine compared the effects of TREM2 +/+ (intact TREM2 function) and TREM2 -/- (loss of function) in mice that were genetically modified to express only tau pathology in their brains4.

After nine months, the mice that were TREM2 +/+ exhibited significantly more brain atrophy compared to their TREM2 -/- counterparts. TREM2 -/- mice also had more quiescent microglia. Unlike the case for amyloid-beta plaques, it appeared that an underactive immune response was crucial in sparing neurons when it came to tau proteins4.

Immune cells are more activated (red) in the brains of mice with the gene TREM2 (left) than in those without the gene (right). A new study shows that having a working copy of the gene TREM2 can reduce risk of Alzheimer’s disease under certain conditions but worsen disease in others. Photo credit: David Holtzman Lab/Washington University School of Medicine
Immune cells are more activated (red) in the brains of mice with the gene TREM2 (left) than in those without the gene (right). A new study shows that having a working copy of the gene TREM2 can reduce risk of Alzheimer’s disease under certain conditions but worsen disease in others. Photo credit: David Holtzman Lab/Washington University School of Medicine

Inflammation: A double-edged sword in AD

These results highlighted the dual roles that inflammation has in AD. “This damage doesn’t have to do with tau aggregation necessarily, but with the immune system’s response to the aggregation,” said graduate student Cheryl Leyns, the study’s co-first author5.

An important caveat in this study is that it only tests the effect of TREM2 mutations on tau proteins. In actual AD, both amyloid plaques and tau proteins co-exist. Besides that, both types of pathologies appear at different stages of the disease4.

Amyloid plaques deposit themselves during early AD. This is when an intact immune system is vital. However, a prolonged excessive immune response may be detrimental later on, when tau proteins start appearing4.

“Maybe that’s why when you have less TREM2 function, you’re at higher risk of developing Alzheimer’s. Less TREM2 function exacerbates amyloid-related injury. But then once the disease progresses and you start to have tau aggregation, it seems that activated microglia become harmful,” adds the team5.

In accordance to the researchers’ hypothesis, it may be that a loss of function in the TREM2 gene has an overall deleterious effect. Mutations in the TREM2 gene have been gaining traction as a significant contributor to the disease process. Whole-genome sequencing performed on populations in Germany, Iceland, the Netherlands, Norway and the U.S. have found strong associations between TREM2 mutations and AD6. Scientists estimate that those with certain types of TREM2 mutations are 3 times more likely to develop AD.

Discovery of TREM2 – a potential therapeutic target

Targeting TREM2 may be trickier than expected. “You might want to activate microglia early on, when people are just beginning to collect amyloid,” said senior author David Holtzman, MD. “If they’re already developing symptoms, then they’re later in the disease process, so you’d probably want to suppress microglia5.”

The exact pathophysiologic mechanisms of AD have bewildered scientists for decades. Despite the demonstration of many different pathways in AD, interactions between them are complex and not fully known. The complexity of the disease is exemplified in these TREM2 experiments – where a single mutation has incongruous effects on different facets of AD.

“TREM2 is so poorly understood that it is too early to say how it might contribute to disease,” commented Dr Richard Ransohoff, a prominent researcher in the field of neuroinflammation7. MIMS

Read more:
More to Alzheimer’s disease than just amyloid plaques
5 major Alzheimer’s research findings announced at AAIC 2017
Dr Alzheimer: All but forgotten

Sources:
1. https://www.nature.com/news/alzheimer-s-disease-the-forgetting-gene-1.15342
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317331/
3. https://www.ncbi.nlm.nih.gov/pubmed/24493463
4. http://www.pnas.org/content/early/2017/10/04/1710311114.full
5. https://medicine.wustl.edu/news/alzheimer-gene-poses-both-risk-and-benefits/
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876682/
7. http://www.alzforum.org/news/research-news/enter-new-alzheimers-gene-trem2-variant-triples-risk