TREM2: Role in Modulating Amyloid Beta and Tau-Related Pathologies and Neurodegeneration

2017, 2019

2019

The TREM2 gene provides instructions for making a protein called triggering receptor expressed on myeloid cells 2; the gene first was identified to be involved in the immune system. The role of TREM2 in the body has expanded to involve facilitating the activation of microglia in response to amyloid plaque accumulation in Alzheimer’s disease. TREM2 regulates microglia metabolism and production of the energy currency of the cell, ATP.

The brains of mice that have been genetically modified to have TREM2 knocked out exhibit something called neuritic dystrophy, suggesting that TREM2 plays a neuroprotective role when it comes to preventing amyloidosis. On the other hand, a deficiency in TREM2 in a mouse model for tau accumulation, the P301S mouse model, led to a decrease in microglial activation, but less brain atrophy. This result suggested that TREM2-dependent microglial activation in a tau model for Alzheimer’s disease could be toxic to neurons. Given that loss of function mutations in TREM2 strongly increase the risk of developing Alzheimer’s disease, we sought to investigate the effect of TREM2 on amyloid-dependent tau accumulation. This research project will take advantage of a newly developed technology called the pathological tau seeding model. Our findings indicate that microglia activation around amyloid plaques may serve a protective role by impeding the development of tau-induced neuritic plaques by a mechanism that involves TREM2.

To further examine the impact of TREM2 in neuronal pathology, we have developed a novel technology in which we obtain whole gene expression data from single cells in the brain. This technology enables identification of every cell population in the brain, such as neurons, microglia, astrocytes and oligodendrocytes, based on common gene expression profiles. Moreover, we can identify the presence of altered cell populations. By using this technology, we have demonstrated that accumulation of amyloid beta plaques in mice lacking TREM2 results in the appearance of a new neuronal population indicative of damaged neurons. We now have treated the same mice with a drug, cyclocreatine, that increases the energetic metabolism of microglia. We anticipate this treatment will reduce the population of damaged neurons by restoring microglial functions.

2017

Recently it has become apparent that the innate immune cells in the brain, microglia, play an important role in the overall response during Alzheimer’s disease. Despite the fact that much effort has been expended on ascertaining the precise nature of the role of microglia in AD, much remains unknown. TREM2 is an important molecule expressed by microglia. TREM2 appears essential to maintaining microglial function in AD, and genetic variants of TREM2 have been linked to an increase in the risk of developing late-onset AD. Our work will focus on understanding the role of TREM2 on microglia using two models of AD, a model of the early development of AD and a model that combines both the early- and late-phase pathology in AD. The overall goal of this work is to better understand the role that microglia play in AD and how TREM2 may impact microglial function in AD. In particular, this work will help answer the question of whether a robust microglial response in AD is good, bad or dependent upon the timing of the response relative to the stage of disease. Ultimately these studies hope to inform the development of new and effective treatments for AD.


Funding to Date

$645,000

Focus

Genes to Therapies™ / Stem Cell Drug Screening, Translational Research

Researchers

David Holtzman, M.D.


Marco Colonna, M.D.