Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice

Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in TREM2 signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer's disease (AD). Numerous studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged TREM2-deficient (Trem2-/-) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young Trem2-/- mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged Trem2-/- mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged Trem2-/- mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of TREM2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.SIGNIFICANCE STATEMENT Microglia are innate immune cells of the brain that orchestrates neurodevelopment, synaptic function, and immune response to environmental stimuli. Microglial triggering receptor expressed on myeloid cells 2 (TREM2) signaling plays pivotal roles in regulating these functions and loss of TREM2 signaling leads to increased risk of developing age-related neurologic disorders. However, the neurologic role of TREM2 in normal aging is poorly understood. The results of the present study unveil the positive impacts of TREM2 deficiency on cognitive and synaptic function during aging and suggest that TREM2 may exert detrimental effects on neuronal function. The possibility of age-related negative impacts from TREM2 is critically important since TREM2 has emerged as a major therapeutic target for Alzheimer's dementia.