A new study adds another piece to the TREM2 puzzle by uncovering what happens when TREM2 levels are reduced in both a mouse model of Alzheimer’s disease and in post-mortem human brains. The findings published in Nature Neuroscience are from the laboratory of Dr. Christian Haass and his collaborators including Dr. David Holtzman and Dr. Oleg Butovsky. All three scientists receive funding from Cure Alzheimer’s Fund.
An individual’s risk for Alzheimer’s disease strongly increases if they have a genetic predisposition. One such risk factor is a variant in a gene called TREM2. TREM2 stands for triggering receptor expressed on myeloid cells-2. The last couple of years have seen a dramatic increase in the number of studies linking the inheritance or rare variants of TREM2 to amyloid plaque build-up and the accumulation of hyperphosphorylated tau. Rare variants in TREM2 were discovered using whole-genome sequencing studies. TREM2 is thought to be involved in microglia proliferation and inflammatory gene expression. This recent paper in Nature Neuroscience describes how TREM2 might regulate the innate immune system’s response to amyloid plaques.
Individuals with rare variations in the gene encoding TREM2 have an increased risk for Alzheimer’s disease that is comparable to the risk conferred by having the single APOE4 allele. TREM2 is considered to be in the category of disease-associated genes that are expressed in microglia. It is thought that an increase in TREM2 fragments in the cerebrospinal fluid can indicate changes in inflammatory pathways. This has the potential to serve as an early indicator of the onset of clinical dementia in Alzheimer’s disease.
TREM2 is activated by lipids (fats and cholesterol). The other ligands or signals that activate TREM2 remain to be investigated. APOE (apolipoprotein E) can bind to TREM2 in order to activate it suggesting an interaction. The main roles attributed to TREM2 include inhibition of inflammatory signaling, promotion of cell survival, and regulation of phagocytosis (the engulfment of harmful pathogens and cellular debris).
In the absence of TREM2, amyloid plaque spreading increases. In addition to this increase in plaque formation, the researchers found a decrease in microglial clustering around the newly seeded plaques. Another consequence of reduced TREM2 was a reduction in the presence of ApoE in the amyloid plaques. The brains of individuals with rare genetic mutations in TREM2 have been shown to have reduced ApoE suggesting that this reduction in ApoE may be contributing to the progression of Alzheimer’s disease.
For a more detailed discussion of the role of TREM2 in Alzheimer’s disease, please see the following Review article in Neuron from Dr. Marco Colonna and Dr. David Holtzman:
The research paper itself can be found on the Nature Neuroscience webpage: Loss of TREM2 function increases amyloid seeding but reduces plaque-associated Apoe
Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer’s disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.