Two back-to-back studies on a protein expressed in brain microglia shed new light on how the immune system can combat the buildup of amyloid plaques that cause neurodegenerative disease. The studies focus on TREM2 (triggering receptor expressed on myeloid cells 2), a receptor protein known to be associated with an increased risk in neurodegeneration such as with dementia, Alzheimer’s, and Parkinson’s. Both studies, published earlier this week in Neuron, come from research groups in California, in Sanford Burnham Prebys Medical Research Institute (SBP) and UCLA.Study senior author Huaxi Xu summarizes the two studies: "Our first paper identifies how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer's disease pathogenesis. The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms."In the first study, the authors found that TREM2 binds directly to the amyloid beta (Aβ) oligomers. In comparison, mutated TREM2 that is found in Alzheimer’s cases showed reduced binding. Further investigation showed that removing TREM2 downregulated potassium ion channels, which affects electrical currents associated with the activation of microglial response to Aβ. In the context of primary microglial cultures and in the mouse brain, a deficiency in TREM2 consequently showed an impaired degradation of Aβ. These findings led to the study’s conclusion that TREM2 functions as a key receptor that interacts with Aβ and drives the microglial response. The second study sought to determine if increasing the “TREM2 gene dosage” could improve the progression of Alzheimer’s. In transgenic mice expressing human TREM2, the authors found that “elevated TREM2 expression reduced amyloid burden.” Transcriptomic profiling showed tempering of disease-associated genes and upregulation of reactive microglial genes linked to phagocytosis. Overall, added TREM2-driven cell signaling stopped disease progression and even restored cognitive function. "These studies are important because they show that in addition to rescuing the pathology associated with Alzheimer's disease, we are able to reduce the behavioral deficits with TREM2," says Xu. "To our knowledge, this provides convincing evidence that minimizing amyloid beta levels alleviates Alzheimer's disease symptoms."
Xu mentions new clinical possibilities for TREM2. "Going after microglia, rather than amyloid beta generation, may be a new research avenue for Alzheimer's disease. We could use brain immune cells to solve what's becoming a public health crisis."