Understanding the biology of Alzheimer’s disease

Unraveling the connections between TREM2, microglia, and neurodegeneration

By Karel Otero Gutierrez, Ph.D.
Group Leader, Department of Neuroimmunology and Acute Neurology

July 18, 2017

Nearly 50 million people worldwide suffer from Alzheimer’s disease (AD), a number that is projected to skyrocket in the coming decades. Because of the overwhelming costs of AD, both human and financial, there are intensive efforts underway to dissect the underlying biology of the disease and apply that knowledge toward the development of novel therapies that can slow or halt its progression.

Observing a gene and its importance to AD
Here at Biogen, we are looking to understand some of the most puzzling biological mysteries about AD. One of these mysteries concerns a gene called TREM2. During the last five years, it was discovered that a handful of variants in this gene are associated with a higher risk of AD. One TREM2 variant in particular, known as R47H, can triple a person’s risk of developing the disease. This was an extraordinary finding that underscores the importance of this gene in AD. Moreover, because it flows from human studies — not research conducted in disease models or tissue culture cells, for example — we believe TREM2 represents a compelling potential target for therapeutic development.

Understanding TREM2, microglia, and neurodegeneration
Despite this excitement, TREM2 remains poorly understood. No one fully understands how it functions or how it contributes to AD. What we know for certain is that the gene is active in a type of support cell in the brain known as microglia. These cells are not neurons, but instead are related to the immune system. Exactly how they behave in the brain remains an active area of investigation, but there are several hypotheses about how microglia might help trigger neurodegeneration and AD. These include defects in the cells’ homeostatic or neuroprotective capabilities, abnormal activation leading to neuroinflammation, and impairments in how the cells physically isolate or wall off the brain from the toxic substances that can build up over time.

Exploring molecular connections
To begin to address these questions, we have been exploring the biology of TREM2 at a molecular level. Earlier studies hinted that TREM2 could function as a kind of partner or co-receptor for a pair of important growth factors, which help to promote microglia survival and growth. These growth factors, known as CSF-1 and IL-34, and their primary receptor, called CSF-1R, have been shown to block some key aspects of AD in disease models, namely the accumulation of amyloid plaques.

Our data suggests that TREM2 cooperates with CSF-1R by physically associating with it and also amplifying the signals it sends when it binds to microglial growth factors. Importantly, it appears that the disease-causing TREM2 variants interfere with these activities — with R47H, TREM2 no longer associates with its partner, CSF-1R.

Visualizing a new approach for AD and neurodegeneration
We still have much to learn about TREM2, microglia and neurodegeneration more generally, but these results are already teaching us some important lessons. Ultimately, our goal is to uncover a broadly applicable therapy that modifies TREM2 function and helps rejuvenate microglia in the brain.

This could prove helpful not just for those patients who carry pathologic TREM2 variants — which are relatively rare, and found at a frequency of 0.1 – 0.4% in Caucasian populations — but also for many others who suffer from AD. Moreover, it is possible that TREM2 contributes to other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and frontotemporal dementia. It is my sincere wish that our research can help reduce the global burden of these devastating illnesses and protect the aging brain.

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