Alzheimer's disease research finds TREM2 deficiency mitigates brain damage induced by tau pathology
Recent studies have uncovered that genetic variants in TREM2 confer a significant risk of Alzheimer's disease. Loss of TREM2 function enhances the neurotoxicity of amyloid-beta plaques, suggesting that TREM2 is protective in the response to amyloid pathology. But the effect of TREM2 on another mechanism of Alzheimer's disease, tau pathology, has not been well defined.
A scientific team headed by Cheryl Leyns and Jason Ulrich from Washington University School of Medicine set out to address this question. Described in the Proceedings of the National Academy of Sciences, their work uncovers that TREM2 deficiency reduced neuroinflammation and brain atrophy in a mouse model of tau pathology. To conclude, loss of TREM2 function is protective in the setting of tau tauopathy.
Combined with previous studies, this work shows that TREM2 has dual roles in Alzheimer's disease. It appears that TREM2 function is important for mitigating amyloid-beta toxicity early in Alzheimer's disease, but it becomes detrimental following the onset of tau pathology later in the disease. Thus, activating it early in the disease and inhibiting it later may be a therapeutic strategy.
Targeting TREM2 has already been proposed as a potential way to treat Alzheimer's disease, but whether to activate or inhibit it remains controversial. This work establishes that TREM2's effects in Alzheimer's disease are associated disease stages as well as the types of pathology.
TREM2 is mainly expressed in microglia, the primary immune cells of the brain that destroy pathogens as well as remove damaged cells. Understanding the functions of TREM2 during the progression of Alzheimer's disease could help understand disease pathogenesis and develop new therapies.